JPS6039072B2 - N-substituted phenylamino fatty acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel N-substituted phenylamino fatty acid derivative having an anti-inflammatory effect, and more specifically, the present invention relates to a novel N-substituted phenylamino fatty acid derivative having an anti-inflammatory effect. is substituted with a hydrogen atom, a halogen atom, a nitro group, an amino group, a cyclolower alkyl group, a lower alkoxy group, a phenoxy group, an anilino group, an N-acetylanilino group, a benzyl group, a mono- or dibenzylamino group, or a halogen. optionally a penzoyl group, a lower alkoxy-substituted penzoylamino group, a tetrazolyl group, a benzothiazolyl group, a penzothiazolyloxy group or a pyridyloxy group, R4 is a hydrogen atom or a lower alkanoyl group, and R5 is a lower alkylene group or a phenylmethylene group, respectively. and the phenoxy group of R3 may be substituted with a halogen atom, a halo-lower alkyl group, or a lower alkyl group, and when R3 is a hydrogen atom, R4 is a lower alkanoyl group). N-substituted phenylamino fatty acids, their salts and nitriles,
It relates to derivatives at the carboxy group selected from amides and lower alkyl esters.

In the general formula (1) representing the object compound (1) of this invention, the halogen atoms represented by R,, R2 and R3 include fluoro, chloro, from and iodo; Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, bentyl, hexyl, and the like.

Further, in general formula (1), examples of the cyclo lower alkyl group represented by R3 include cyclopropyl, cyclobutyl, cyclobentyl, cyclohexyl, cycloheptyl, etc., and examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isof.

o poxy, butoxy, isobutoxy, tertiary butoxy,
Examples include benzyloxy and hexyloxy. R3
Examples of the halogen atom and lower alkoxy group in the optionally halogen-substituted penzoyl group and the lower alkoxy-substituted penzoylamino group represented by are the same as those mentioned above. Examples of the lower alkanoyl group represented by R4 in the general formula (1) include alkanoyl groups such as formyl, acetyl, propionyl, butyryl, bentanoyl, hexanoyl, and pivaloyl.

Among the substituents represented by R3, the phenoxy group includes the above-mentioned halogen atoms, lower alkyl groups, and chloromethyl, bromomethyl, iodomethyl, dichloromethyl,
C. Dichloroethyl, trifluoromethyl, etc.

It may be optionally substituted with a lower alkyl group, and when two or more of these substituents are present, they may be the same or different. Furthermore, in the general formula (1), the lower alkylene group represented by R5 is:
Straight chain or branched alkylene groups such as methylene, methylmethylene, dimethylmethylene, ethylene, propylene, trimethylene, tetramethylene, bentamethylene, and hexamethylene are exemplified.

Examples of the salts of these N-substituted phenylamino fatty acids (1) include alkali metal salts such as sodium salts and potassium salts, salts with organic bases such as triethylamine salts, dimethylaniline salts, and dicyclohexylamine salts. Further, derivatives of the carpoxy group of the N-substituted phenylamino fatty acid (1) include nitrile, amide, and lower alkyl ester, and examples of the lower alkyl ester include methyl ester, ethyl ester, and propyl ester.

The object compound (1) of the present invention is, for example, the general formula (wherein,
R, , R2 and R3 have the same meanings as before, and R'4 means a lower alkanoyl group), the general formula X-R5-COO (m
) (in the formula, R5 has the same meaning as before, and
, R2, R3 and R5 have the same meaning as before, R'4
means a lower alkanoyl group),
obtaining its salts or its derivatives at the carboxy group;
Among target compounds (1), compounds in which R4 is a hydrogen atom in general formula (1) can be produced by further subjecting compound (1') obtained as described above to a hydrolysis reaction.

As the lower alkanoyl group represented by R'4 in the general formula (b) representing the anilide (0) used as a raw material in this reaction, those exemplified above as the lower alkanoyl group for R4 are also exemplified here. .

The general formula (
Typical examples of acid residues represented by X include halogens such as chloro, frome, and iodine; , and residues of acids such as dialkylcarbamic acids.

As the salts of the fatty acid (m) and its derivatives at the carboxyl group, those exemplified above as the salts of the target compound (1) and its derivatives at the carboxyl group are exemplified here as well.

The reaction between anilides (b) and fatty acids (m), their salts, or their carboxyl group derivatives is usually carried out in a solvent under heating, and the solvent may be water, methanol, tetrahydrofuran, dioxane, N-methylmorpholine. ,
Pyridine, dimethylformamide, benzene, toluene, etc. are frequently used, but any other solvent that does not adversely affect this reaction can be used.

This reaction is usually carried out in the presence of a base.
Bases include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate,
Inorganic bases such as potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium hydroxide, calcium hydroxide, magnesium carbonate, calcium carbonate, triethylamine,
Examples include organic bases such as pyridine and dimethylaniline, as well as basic ion exchange resins. Through this reaction, a target compound having a lower alkanoyl group as R'4 in general formula (1') is produced, but a compound having a hydrogen atom as R4 in the target compound (1) can be obtained as described above. Compound (1') can be produced by subjecting it to a hydrolysis reaction.

The hydrolysis reaction of compound (1') is usually carried out using compound (1')
inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; organic acids such as diprotic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid;
Alternatively, it may be carried out by heating in the presence of a mixture of these.

This hydrolysis reaction can also be carried out without particularly isolating or purifying compound (1'). In addition, when the compound subjected to the hydrolysis reaction is a salt of compound (1') or its derivative at the carboxyl group, depending on the reaction conditions, the target compound (
1) may be obtained. Among the target compounds of this invention, the general formula (wherein R3, R4 and R5 have the same meanings as before,
R' and R2 each represent a halogen atom and the other represents a halogen atom or a lower alkyl group), their salts, and their carboxyl group derivatives are, for example, represented by the general formula (in the formula, R3, R4
and R5 have the same meaning as before, R'', and R''
2 is also produced by allowing a halogenating agent to act on a compound, a salt thereof, or a derivative in the carboxy group thereof, in which either one is a hydrogen atom and the other is a hydrogen atom, a halogen atom, or a lower alkyl group. be able to.

As the salts of the compound (W) and its derivatives at the carboxyl group used as raw materials in this reaction, those exemplified above as the salts of the target compound (1) and its derivatives at the carboxyl group are also exemplified here as they are. .

As the halogenating agent used in this method, all of the halogenating agents commonly used in halogenating aromatic compounds can be used. Examples of such halogenating agents include halogens such as chlorine, bromine, and bromine; monochlorides of halogens such as bromine monochloride and bromine monochloride; hypochlorous acid and tertiary butyl hypochlorous acid; Hypohalous acid and its alkyl esters, N-halogenamides such as N-bromoacetamide, N-iodoacetamide, N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride, sulfurylfuromide, sulfurylfuromy cupric halides such as cupric chloride, cupric bromide, pyridinium hydrofuromide/gufuromide, dioxane dibromide, and the like. This reaction is usually carried out in a solvent, and dioxane, benzene, etc. are often used as the solvent, but any other solvent that does not adversely affect this reaction can be used.

Although the reaction temperature is not particularly limited, it is usually carried out at room temperature, under heating, or under heating. When both R'' and R''2 of the starting compound (W) are hydrogen atoms, it is desirable to use the halogenating agent in an amount of at least twice the mole of the compound (W).

In addition, R'',, R''2 and R of the starting compound (W)
3 are all hydrogen atoms, R', and R
In addition to 2, a compound (r) in which R3 is also a halogen atom may be obtained, and in this case, it is desirable to use the halogenating agent in an amount of at least 3 times the molar amount of the starting compound (W). In addition, when producing a compound (1'') in which R3 is an anilino group or pendylamino group by this reaction,
A compound in which the amino moiety of the anilino group or pendylamino group of R3 in compound (N) is protected with a removable protecting group may be used as a raw material, and the protecting group may be removed after the halogenation reaction.

Examples of protective groups that can be applied in this case include common N-protecting groups such as formyl, acetyl, tertiary-butoxycarbonyl, benzyloxycarbonyl, and tosyl, and these N-protecting groups can be removed using conventional methods. This is done by In addition, if a compound (N) in which R3 in the general formula (W) is a phenoxy group or a penzoyl group is used as a raw material and this reaction is performed, a compound in which the phenyl moiety in the substituent of R3 is also halogenated is obtained. There is also.

Furthermore, among the target compounds of this invention, general formula (wherein R
, , R2, R4 and R5 have the same meaning as before, R'
3 means a mono- or dibenzylamino group), its salts and its derivatives at the carboxy group are, for example, represented by the general formula (wherein R., R2, R4 and R5 have the same meanings as before). The compound having the general formula R″31
(In the formula, R''3 means a pendyl group and X' means an acid residue, respectively.) It can be produced by reacting with a compound represented by the following formula.

The salts of compound (V) used as a raw material in this reaction include those exemplified as the salts of the target compound (1) above, as well as salts at the amino group such as hydrochloride, hydrobromide, and p-toluenesulfone. Acid salts such as acid salts are also exemplified.

Further, as derivatives at the carboxy group of compound (V), those exemplified as the derivatives at the carboxy group of the target compound (1) above are exemplified here as well, and as derivatives at the amino group, compound (V) and trimethylsilicate Examples include reaction products with silyl compounds such as chloride and bis(trimethylsilyl)acetamide. In compound (W), which is the other raw material, the acid residue represented by X' is exemplified by the same acid residue as the acid residue represented by X in compound (m).

Further, this reaction is carried out in the same manner as the reaction between compound (0) and compound (m) described above. In addition, when two pendyl groups are introduced onto the amino group in this reaction, it is usual to use twice the molar amount of compound (V) relative to compound (V). Furthermore, among the target compounds of this invention, compounds represented by the general formula (wherein R,, R2, R4 and R5 have the same meanings as above, and R...3 means a lower alkoxy group-substituted penzoylamino group) , its salts and its derivatives at the carboxy group are, for example, compound (V), its salts or its derivatives at the amino group or the carboxy group having the general formula R -OH
It can also be produced by reacting with a compound represented by the following formula (R'''3 means a lower alkoxy-substituted penzoyl group) or a reactive derivative thereof.

The salts of compound (V) used as raw materials in this reaction and the derivatives thereof at the amino group or carboxy group are as described above. Examples of reactive derivatives of the compound (dish) that is the other raw material include acid halides such as acid chloride and acid bromide, as well as activated amides and activated esters.

This reaction is usually carried out in a solvent, and any solvent such as pyridine that does not adversely affect this reaction can be used. Although the reaction temperature is not particularly limited, the reaction usually proceeds satisfactorily at room temperature. This reaction can be carried out in the presence of a condensing agent commonly used in acid amide bond forming reactions, or in the presence of a base such as pyridine, triethylamine, or N,N-dimethylaniline. good. The products of the various reactions mentioned above are isolated and purified by conventional methods, but if the reaction product is a derivative with a carboxy group, it may be subjected to a hydrolysis reaction to form a free carboxylic acid, if desired. You can guide me.

This hydrolysis reaction is usually carried out in a solvent such as water or aqueous methanol at room temperature or under heating by the action of a base or acid, but the solvent and reaction temperature are not limited thereto.

Bases used here include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium alkoxide,
Inorganic or organic bases such as potassium alkoxide are often used, and acids include inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc. are often used, but the bases and acids are not limited to these, and for example, basic or acidic ion exchange resins may also be used. Furthermore, among these bases and acids, liquid ones may be used also as a solvent. On the other hand, when the reaction product obtained in the various reactions described above is a free carboxylic acid, it can be converted to the desired salt or nitrile, as described above, by a conventional method.
It may also lead to derivatives at the carboxy group selected from amides and lower alkyl esters.

The object compound (1) of this invention includes the following compounds in addition to those obtained in the examples, and these compounds can also be produced according to the above-mentioned method.

N-[2,6-dichloro-4-(2-pyridyloxy)
phenyl) glycine N-[2,6-dichloro4-(2
-pyrimidinyloxy)phenyl]glycine N-[2,
6-jiku.

Rho 4-(2-thiazolyloxy)phenyl]glycine N-[2,6-dichloro-4-(3,5-xylyloxy)phenyl]glycine N-[2,6-dichloro-4-
(2,5-xylyloxy)phenyl]glycine N-[
2,6-dichloro-4-(2,4-xylyloxy)phenyl]glycine N-[2,6-dichloro-4-(3-
Hydroxyphenoxy)phenyl]glycine N-[2,
6-dichloro-4-(2-fluorophenoxy)phenyl]glycine N-[2,6-dichloro-4-phenylthiophenoxy)glycine Next, the object compound of this invention (
The anti-inflammatory effect test (guinea pig ultraviolet erythema method) conducted for 1) will be explained.

Experimental method Male guinea pigs of the Hartree strain, 5 weeks old, weighing approximately 350 kg, were used as experimental animals, with 10 animals per group.
I took it as a fish.

A cloth with 3 holes on the 9-diameter side was placed on the back of the guinea pig from which hair had been removed, and the distance from the skin to the skin layer was 13 arcs from a Hanovia 500W ultraviolet lamp, and the cloth was irradiated for 80 seconds to show obvious erythema. Things are 1. Things with unclear boundaries are 0.
5 If almost no erythema was observed, it was scored as 0, and since the total of the three sites was always 2 or more in the control group, those with a total score of 1.5 or less were judged to be effective.

The evaluation is when there are no effective cases after administration of 9/k9 of 500 (1), when there are 7 or fewer effective cases (10), when there are 8 or more effective cases (10), or 8/k9 of 125. When the number of effective cases is 8 or more after administration (T), When the number of effective cases is 8 or more after administration of 32 days/kg (M), When the number of effective cases is 8 or more after administration of 9/k9 of 8
When there were more than one animal, it was defined as (book).

The samples were prepared by dissolving each sample in a 0.5% methyl cellosolve aqueous solution so that the dose of each sample was a predetermined amount and the amount of solution administered was Z/k9 of 20.

Half of this sample was orally administered one hour before irradiation, and the other half immediately after irradiation. The effectiveness was evaluated 2 hours after irradiation.

Experimental Results: As is clear from the above experimental results, the object compound (1) of the present invention has an anti-inflammatory effect and is effective as a medicine.

When using this as a medicine, it is usually administered in the form of oral preparations such as tablets, granules, powders, capsules, syrups, injections, suppositories, etc. 10 to 2,000 times a day, 10 to 2,000 times a day. 5
00 o is administered. This dosage is adjusted as appropriate depending on the patient's age, body weight, symptoms, or mode of administration. In addition, various formulations such as those mentioned above can be prepared using commonly used carriers.
It can be manufactured in a conventional manner. Next, "Production examples of the object compound (1) of the present invention will be explained with reference to Examples.

Example 1 {1'N-(4-phenoxyphenyl)glycine ethyl ester 11.0 and N-chlorosuccinimide 1
0.859 was dissolved in 150% dioxane and heated at 70°C. Pray for some time.

To this, add 5.0 ml of N-chlorosuccinimide,
Continue worshiping at the same temperature for another hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. After washing the extract with water and drying over magnesium sulfate, the solvent is removed under reduced pressure. The oily residue was subjected to silica gel column chromatography using a hexane and benzene solution (1:
Elution with 1) gives 8.50 g of pale yellow, oily N-(2,6-dichloro-4-phenoxyphenyl)glycine ethyl ester. Infrared absorption spectrum (liquid film method) ymaX arc-1: 3400, 1750 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 1.28 (group, t, J = 7H
Z) 4.06 (2 days, s) 4.23 (2 days, q, J=7
HZ) 4.67 (IH, broad s) 6.80-7.50 (7 days, m) [2'N-(2,6-dichloro-4-phenoxyphenyl)glycine ethyl ester obtained above 7.0 ml of sodium hydroxide is dissolved in 100 ml of methanol solution containing 4.0 ml of sodium hydroxide and allowed to stand for 1 hour at room temperature.

The reaction solution was concentrated under reduced pressure, and 300 g of water was added to the remaining solution. Concentrated hydrochloric acid was added to this aqueous solution to bring it to pHI, and the mixture was extracted with ether. After washing the extract with water and drying over magnesium sulfate, the solvent is removed under reduced pressure. The obtained crystal is n-
Recrystallization from a mixture of hexane and ethyl acetate yields N-(
5.0 kg of colorless needle-like crystals of 2,6-dichloro-4-phenoxyphenyl)glycine are obtained. mpll0-111℃.

Elemental analysis: C, 4 days. N02CI2 Calculated value: C53.86, day 3.55, N4.49, CI
22.72 Experimental value: C53.76, day 3.48, N4.
47, CI22.63 infrared absorption spectrum (Nujol method) maXC -1:3390,2600-300
0,1730 nuclear magnetic resonance absorption spectrum 6 (DMSO-
d6) ppm: 4.08 (2 days, s) 6.82-7.6
0 (7 days, m) Example 2 {1} 5.50 g of N-(4-penzoylphenyl)glycine ethyl ester and 5.20 g of N-chlorosuccinimide are dissolved in 50 g of dioxane, 3. At 100℃. The morning hours are intense.

The reaction solution was concentrated under reduced pressure, water was added to the residual light, and then extracted with ether. After washing the extract with water and drying with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain N-(2,
6.0 crystals of 6-dichloro-4-benzoyl phenyl)glycine ethyl ester were obtained. mP94-9500
.

Infrared absorption spectrum (Nujol method) ShimaXC 1: 3390, 1740 Nuclear magnetic resonance absorption spectrum 6 (DMSO-Q) ppm: 1.20 (Team, t, J = 7
Hz) 4.13 (ga, q, J = 7HZ) 4.61 (IH, s) 7.60 (7 days, m) ■ N-(2,6-dichloro-4-penzoylphenyl) obtained above A methanol solution containing 6.0 g of glycine ethyl ester and 4.0 g of sodium hydroxide was added to 150 g of methanol solution.
and incubate for 2 hours at room temperature.

The solvent was removed from the reaction solution under reduced pressure, water was added to the residue,
After washing with ether, make PHI with concentrated hydrochloric acid and extract with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. When the obtained crystals are recrystallized from a passing solution of n-hexane and ethyl acetate, N
4.6 M of colorless crystals of mono(2,6-dichloro-4-penzoylphenyl)glycine are obtained. mp184~185o
0. Elemental analysis: C, 5 days. N03CI2 Calculated value: C55.58, day 3.42, N4.32 Experimental value: C55.59, day 3.29, N4.25 Infrared absorption spectrum (Nujol method) maX skin-1: 3400,
1720, 1640 nuclear magnetic resonance absorption spectrum 6 (DM
SO-&) ppm: 4.45 (2 days, t, J=6HZ)
6.25 (IH, t, J=6HZ) 7.68 (7 days, m) Example 3 {1'N-[4-tetrazol-1-yl)phenyl]glycine ethyl ester 6.50 and N - Dissolve 8.1 liters of chlorosuccinimide in 100 ml of dioxane and heat at 70 qo for 3 hours.

The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting crystals are recrystallized from ethanol to obtain 6.80 g of N-[2,6-dichloro-4-(IH-tetrazol-1-yl)phenyl]glycine ethyl ester. mp12
6-127o0. Infrared absorption spectrum (Nujol method) ma
6HZ) 3.50 (ga, q, J = 6HZ) 3.67 (2 days, d, J = 6HZ) 4.90 (IH, t, J = 6HZ) 6.60 (IH, s) 8.33 (IH,s) ■ 6.80 g of N-[2,6-dichloro-4-(IH-tetrazol-1-yl)phenyl]glycine ethyl ester obtained above was added to 50 g of acetic acid and 5 g of concentrated hydrochloric acid. Dissolve in a mixture of 1. Heat to reflux for an hour.

The solvent was distilled off from the reaction solution under reduced pressure, and the resulting crystals were washed with water, air-dried, and then recrystallized from ethanol to obtain N-
[2,6-dichloro-4-(IH-tetrazole-1-
3.70 g of colorless needle-like crystals of phenylglycine were obtained. mp20500 (disassembled). Elemental analysis: C9 day 7N5
02CI2 Calculated value: C37.52, day 2.45, N24.31, C
I24.61 experimental value: C37.56, day 2.37, N2
4.19, CI24.45 Infrared absorption spectrum (Nujol method) ma
HZ) 5.83 (IH, t, J = 6HZ) 7.91 (2 days, s) 9.10 (IH, s) Example 4 {1} N-(4-cyclohexylphenyl) glycine ethyl ester 5 0 and N-chlorosuccinimide were dissolved in 70% dioxane and diluted at 7500°C.
I waste time.

The reaction solution was concentrated under reduced pressure, and 100 g of water was added to the residue, followed by extraction with 100 ml of ether and 50 ml of ether, respectively. The ether extracts were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give an oily N-(2,6-dichloro-4-cyclohexylphenyl)glycine ethyl alcohol. Get 6.70 evenings.

Infrared absorption spectrum (liquid film method) maXC 1:3
400,1740 Nuclear magnetic resonance absorption spectrum 6 (CC14) ppm: 1.25 (9 days, t, J = 6H
Z) 1.33-2.50 (11 days, m) 3) 57 (2 days, s) 4.17 (2 days, q, J=6HZ) 7.0 (2 days, s) [21 above 6.70 μl of the obtained N-(2,6-dichloro-4-cyclohexylphenyl)glycine ethyl ester was added to 70 μm of an aqueous solution containing 3.5 μl of sodium hydroxide, and incubated at 10,000 °C for 1 hour. .

After washing, the reaction solution was washed with 50% of ether, adjusted to pHI with concentrated hydrochloric acid, and extracted with ether.The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The oily residue was dissolved in 50% aqueous sodium bicarbonate solution, washed with ether, brought to pHI with concentrated hydrochloric acid, and extracted with ether.The extract was washed with water and dried over magnesium sulfate. Thereafter, the solvent is removed under reduced pressure.The oily residue is treated with a slurry of benzene and n-hexane to powder.The resulting powder 2.109 is dissolved in 50 parts of ethyl acetate, and acetic acid is added to this. Methanol solution containing 9 parts of 800 sodium 20
Add feathers. This is concentrated under reduced pressure and the residue is triturated with ether. The resulting powder is 2.20 ml of water and 30 ml of water.
Recrystallization from the solution gives 1.50 g of white crystals of sodium N-(2,6-dichloro-4-cyclohexylphenyl)glycine. mp23000 or more.

Elemental analysis: C, 4 days, 6N02CI2Na Calculated value: C5
1.86, day 4.98, N4.32 Experimental value: C50.1
4, Sun 4.89, N4.17, Sun 200.76 infrared absorption spectrum (Nujol method) maxc -1:31
80,1710 (shoulder), 1610 nuclear magnetic resonance absorption spectrum 6 (DD300) ppm: 1.0-1.67 (10
day, m) 2.0 (IH, broad s) 3.25 (2
5.93 (ga, s) Example 5 {1) N-[4-(2,6-xylyloxy)phenyl]glycine ethyl ester hydrochloride (10.0 g) was added to an aqueous sodium bicarbonate solution. Dissolve and extract with table.

After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an oil containing N-[4-(2,6-xylyloxy)phenyl]glycine ethyl ester, which was diluted with 90% dioxane. dissolve in 11.7 hours of N-chlorosuccinimide was added to this solution and heated at 30°C for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure. The oily residue was purified by silica gel column chromatography to give an oily N-[2,6-dichloro-4-(2,6-dichloro-4-(2,
3.0% of 6-kylysyloxy)phenylglycine ethyl ester is obtained. Infrared absorption spectrum (liquid film method) ShimaX skin-1: 3370, 1745, 1600 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1.28
(So, t, J=6HZ) 2.12 (Navy blue, s) 4.03 (
2nd, d, J = 6Hz) 4.24 (2nd, q, J = 9Hz) 4.52 (IH, t, J = 6Hz) 6,70 (ban, s) 7.08 (so, s) (2} N-[2,6-dichloro4-(2
,6-xylyloxy)phenyl]glycine ester 3
．． The solution was dissolved in 40 ml of methanol solution containing 1.0 ml of sodium hydroxide and incubated at room temperature for 2.5 hours.

The reaction solution is concentrated under reduced pressure, water is added to the isosumi, and the mixture is washed with ether. This aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. When the obtained crystals are recrystallized from a mixture of ethyl acetate and n-hexane, N-(
2,6-dichloro. 2.6 hours of white crystals of -4-(2,6-xylyloxy)phenyl]glycine are obtained. mp15
6-15800.

Elemental analysis: C, 6 days, 5N03CI2 Calculated values: C56.49, days 4.44, N4.12, CI
20.84 Experimental value: C56.52, day 4.35, N4.
30, CI21.10 infrared absorption spectrum (Nujol method) maXC -1:3320,1745,160
0,1495 nuclear magnetic resonance absorption spectrum 6 (DMSO-
d6) ppm: 2.15 (fine, s) 4.03 (group, s)
6.68 (2 days, s) 7.18 (3 days, s) Example 6 ○) N-[4-chlorophenoxy)phenyl]glycine ethyl ester 20.3 days and N-chlorosuccinimide 20 Dissolve 400g of dioxane in 200g of dioxane,
I worshiped flies for 1 hour at OO and 1.5 hours at 55 C○.

The solvent was distilled off from the reaction solution under reduced pressure, 200 parts of water was added to the residue, and the mixture was extracted with 200 parts of ethyl acetate. The extract is washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is removed under reduced pressure. When the obtained crystals are recrystallized from ethanol, N-[2,6-dichloro-
17.10 hours of white crystals of 4-(4-chlorophenoxy)phenylglycine ethyl ester are obtained. mp82~
84.500. Infrared absorption spectrum (Nujol method) ShimaX skin-1:3400, I? 40 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1.10 (so, t, 1 = 6 days 2) 3.41 (crime, s) 3.53 (2 days, q, J = 6H
Z) 3.91 (IH, broad s) 5.83 (2 days, s) 6.10, 5.80 (2 days, ABq, J = 6 days 2) (2} N-[2 ,6-dichloro-4-(4
-chlorophenoxy)phenyl] 16.8 g of glycine ethyl ester was suspended in 100 g of methanol and stirred at room temperature.

To this was added 50 methanol solution containing 9.0 m of sodium hydroxide, and 1.5 methanol solution was added at room temperature. I worship insect time hina. The reaction solution was concentrated under reduced pressure, 50 parts of water was added to the residue, and 20% of ether was added.
Wash with 00'. The aqueous solution is made acidic with concentrated hydrochloric acid and extracted with 200 ml of ether. The extract was washed with water, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting crystals were recrystallized from a mixture of ethyl acetate and n-hexane to give N-[2,6-dichloro4- 10.80 g of crystals of chlorophenoxy)phenylglycine were obtained. mp132-13y0. Elemental analysis: C, 4th, Bu03
CI3 Calculated value: C48.51, day 2.91, N4.04, CI
30.69 Experimental value: C48.51, day 2.72, N4.
05, CI30.74 Infrared absorption spectrum (Nujol method) maX skin-1: 3400, 1710 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 4.21 (ga, s) 6.91
(2nd, s) 6.95, 7.33 (phantom, ABq, J = 12HZ) {3} N-(2,6-dichloro-4-(4
-chlorophenoxy)phenyl]glycine (4.0 g) was dissolved in 50 g. of methylene chloride.

To this was added 1.179 g of triethylamine, and the mixture was incubated in an ice-salt bath to bring the temperature to -5°C. A methylene chloride solution containing 1.25% of ethyl chloroformate was added dropwise to this, and the mixture was incubated at -2 to -3°C for 20 minutes. Ammonia gas is introduced into this at the same temperature, and the mixture is stirred for 1 hour. When the precipitated crystals are collected in a furnace, N-[2,6-dichloro-4-(4-chlorophenoxy)phenyl]glycinamide is obtained.
After washing the methylene chloride layer of the furnace solution with water and drying it with magnesium sulfate, the solvent was removed under reduced pressure. When the residue and the crystals collected earlier are combined and recrystallized from ethanol,
Obtain 2.20 hours of white crystals of this product. mpl38.5~1
40. Zu○. Elemental analysis: C, 4 days. N202CI3 Calculated value: C48.65, day 3.21, N8.11 Experimental value: C48.59, day 3.12, N8.12 Infrared absorption spectrum (Nujol method) maX skin 1:3400,
3200, 1630 nuclear magnetic resonance absorption spectrum 6 (DM
SO-&) ppm: 3.90 (ga, d, J=5HZ)5
．． 30 (IH, t, J=5HZ) 6.90-7.70 (unit, m) Example 7 {1} N-[4-(3-trifluoromethylphenoxy)phenyl] glycine ethyl ester 10. 79 and N-chlorosuccinimide at 9.7 m and dioxane at 10 m
In addition to '0', worship at 600C for 30 minutes.

The solvent was removed from the reaction solution under reduced pressure, 150% water was added to the residue, and the mixture was extracted twice with 100% ether ash. After washing the extract with water and drying over magnesium sulfate, the solvent is removed under reduced pressure. The oily residue was purified by silica gel column chromatography and eluted with a mixture of benzene and n-hexane (1:1).
- 10.40 g of white crystals of [2,6-dichloro4-(3-trifluoromethylphenoxy)phenyl]glycine ethyl ester were obtained. mp39.5-41°C. Infrared absorption spectrum (Nujol method) -1 of maXC: 3190,1750 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 1.10 (group, t, J = 6 days 2) 3.43 (but, d, J Monkey 4th 2) 3.58 (2nd,
q, J = 6 days 2) 3.98 (IH, t, J = 4HZ) 5.83 (bait, s) 5.90-6.33 (4 days, m) {2} N- obtained above [2,6-dichloro 4-1 (3
-trifluorophenoxy)phenyl]dalicin ethyl ester was dissolved in 100% methanol,
A methanol solution containing 7.1 g of potassium hydroxide in this
Add 0' and let it stand at room temperature for 1 hour.

Methanol was distilled off from the reaction solution under reduced pressure, and the residue was diluted with water.
Add 00 cry and wash with ether. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. After washing the extract with water and drying with magnesium sulfate, the solvent is removed under reduced pressure. The resulting crystals were recrystallized from a solution of ethyl acetate and n-hexane to give N-[2,6-dichloro-4-N-(3
4.9 hours of white crystals of -trifluoromethylphenoxy)phenyl)glycine are obtained. mp123-124.50
0. Elemental analysis: C, 5th, state 03CI2F3 Calculated value: C47.39, day 2.65, N3.68, CI
18.65, F14.99 Experimental value: C47.17. day 2
．． 49, N3.85, CI18.89, F15.28 Infrared absorption spectrum (Nujol method) -1 of maXC: 3390, 1735 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 4.20 (but, s) 7. 00
(2 days, s) 7.20-7.60 (4 days, m) 7.67 (bait, broad s) Example 8 (1) N-[4-(2-penzothiazolyl)phenyl] glycine ethyl ester 17 0.0 ml and 15.27 ml of N-chlorosuccinimide are dissolved in 200 M dioxane and lampified at 60 DEG C. for 1 hour and 20 minutes.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved on 400 ml of ethyl acetate. This is washed with water, then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to a liquid volume of about 100'. Add n-hexane to this concentrated solution and leave it at room temperature. The precipitated crystals are collected in a furnace, washed with a mixture of ethyl acetate and n-hexaso, and dried to give N-[2,6-dichloromethane]. Low 4-(2-
Crystals 19.09 of pensothiazo1'l)phenyl]glycine ethyl ester are obtained. mpl18-122℃. Infrared absorption spectrum (Nujol method) ShimaXC-1:3440,1746,1608 nuclear magnetic resonance absorption spectrum 6 (DMSO-4) ppm: 1
, 20 (zu, t, J = 7, 8 days 2) 4.20 (ga, q,
J=7,8 Hz) 4.30 (2 days, d, J=7HZ) 6.38 (IH, t, J=7HZ) 7.44 (crime, m) 8.00 (ga, m) {2 ) N-[2,6-dichloro-4-(2
10 parts of -benzothiazolyl)phenylglycine ethyl ester are added to a solution consisting of 6 parts of potassium hydroxide and 100 parts of water.

After adding 150 methanol to this while stirring, the mixture was concentrated at room temperature for 4 hours and at 6,000 methanol for another 2 hours. The reaction solution is concentrated under reduced pressure, and water is added to the residue. The precipitate was collected in a furnace, suspended in water, and made acidic by adding concentrated hydrochloric acid.
The resulting crystalline precipitate is filtered off. The furnace solution was diluted with ethyl acetate.
After extraction is carried out twice, the extract is washed with water and dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting crystalline residue was combined with the crystallized land precipitate taken out in the furnace, and 80% of ethyl acetate was added.
Heat and dissolve on top of 00. The solution is concentrated under reduced pressure to about half its volume. Add n-hexane to this concentrated solution and leave it at room temperature. When the precipitated crystals are collected in a furnace, N-[2
, 6-dichloro-4-(2-penzothiazolyl)phenyl]glycine 4.0% is obtained. mp233-235q0
.

Elemental analysis: C, 5 days, 202SC12 Calculated values: C51.01, days 2.85, N7.93, CI
20.07 Experimental values: C51.11, day 2.81, N8.
02, CI20.31 Infrared absorption spectrum (Nujol method) HimaX-1:3360,1744,1600
Nuclear magnetic resonance absorption spectrum 6 (DMSO-also) ppm:
4.37 (2 days, d, J = 7 days 2) 5.95 (IH, t
, J=7HZ) 7.48 (ga, m) 7.90 (2 days, s) 8.04 (2 days, m) Example 9 (1) N-[3-(2-benzothiazol-1') phenyl ] Add 6.6 g of glycine ethyl ester and 6 g of N-chlorosuccinimide to 80 g of dioxane,
0 for 1 hour and 20 minutes.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. This solution is washed with water, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The oily residue was subjected to silica gel column chromigraphy and treated with a mixed solvent of ethyl acetate and benzene (
1:10) to produce an oily N
-[2,6-dichloro-3-(2-penzothiazolyl)
4.5 times of phenylglycine ethyl ester was obtained.

Infrared absorption spectrum (Nujol method) maX arc-1: 3440, 1746, 1598 nuclear magnetic resonance absorption spectrum 6 (DMSO-4) ppm: 1.2
5 (thin, t, J = H = 7, 8 days 2) 4.16 (4 days, m
) 6.20 (IH, t, J = 7HZ) 6.86 (IH, d, J = 9HZ) 7.44 (2 days, d, J = 9 days 2) 7.64 (2 days, m) 8 .20 (spots, m) (2} N-[2,6-dichloro-3-(2) obtained above
-benzothiazolyl)phenyl]glycine ethyl ester, 30 g of a methanol solution containing 4.5 g. of salt and 1.7 g. of potassium hydroxide were added, and the mixture was allowed to stand at room temperature for 3 hours and 4 minutes.

Insoluble matter in the reaction solution is removed by a furnace, and the furnace solution is concentrated under reduced pressure.
Dissolve Zanwan in water and add concentrated hydrochloric acid to make it acidic. The precipitated crystals were collected in a furnace, washed with water, dried, and then mixed with ethyl acetate and n
- Recrystallization from a mixture of hexane gives 3.5 ml of N-[2,6-dichloro-3-(2-benzothiazolyl)phenyl]glycine. mp227-230°C (decomposition).
Elemental analysis: C, 5 days, 02SC12 Calculated values: C51.01, days 2.85, N7.93, CI
20.07 Experimental value: C50.77, day 2.89, N7.
85, CII9.90 infrared absorption spectrum (Nujol method) maX skin-1: 3440, 1730, I595
Nuclear magnetic resonance absorption spectrum 6 (DMSO) ppm:
4.04 (2 days, d, J=7HZ) 6.04 (IH, t
, J = 7Hz) 6.84 (IH, d, J = 9 days 2) 7.42 (IH, d, J = 9 days 2) 7.60 (crime, m) 8.22 (2 days, m) Example 10 Hydrochloride of N-[4-(2,3-xylyloxy)phenyl]glycine ethyl ester is treated with an aqueous sodium bicarbonate solution to obtain an educt, which is extracted with ether.

After washing the extract with water and drying with magnesium sulfate, the solvent was removed under reduced pressure to obtain an oily N-[4-(2,3-
xylyloxy)phenyl]glycine ethyl ester is obtained. Add 20 units of dioxane to this. A dioxane solution containing 7.95 μm of N-chlorosuccinimide in this
Drop 0' at 30 to 3y0 over 4 minutes. After the addition was completed, the temperature was flooded to 35 to 37°C, and 0.55°C of N-chlorosuccinimide was added, and the mixture was heated at the same temperature for 1 hour.
The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. N1 [2,6
To the oily residue containing -dichloro-4-(2,3-xylyloxy)phenyl]glycine ethyl ester was added 40 methanol solution containing 3.40 g of potassium hydroxide, and the mixture was heated at room temperature for 1.5 h. At ~35 qo, light up for another 2 hours. The solvent was removed from the reaction solution under reduced pressure, water was added to the residue, and the mixture was washed with ether. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. After drying the extract over magnesium sulfate, the solvent is distilled off under reduced pressure. The resulting crystals are recrystallized from a mixture of n-hexane and ethyl acetate to obtain 2.5 hours of white crystals of N-[2,6-dichloro-4-(2,3-xylyloxy)phenyl]glycine. mp129-130.50○.

Elemental analysis: C, 6 days, 5N03CI2 Calculated value C56.49, days 4.44, N4.12, CI
20.84 Experimental value C56.29, Day 4.32, N4.
10, CI21.05 infrared absorption spectrum (Nujol method) maXC -1:3300,1742,160
5 nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) pp
m: 2.55 (so, s) 2.80 (9th, s) 4.85
(2 days, s) 8.40 (spots, m) Example 11 N-[4-(3-chlorophenoxy)phenyl]glycine ethyl ester 4.50 times and N-chlorosuccinimide 4.6 times dioxane Dissolved in 50 me, 50 qo
So 1. Worshiping the insect time rope.

The reaction solution was added to 100% water and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. N-[2,6-dichloro-4-(3
-chlorophenoxy)phenyl]glycine ethyl ester was dissolved in 5.50 g of methanol and 20 g of methanol.
dissolve in Add 20 parts of a methanol solution containing 1.8 parts of sodium hydroxide to this, and stir at room temperature for 1.5 hours. Concentrate the reaction solution under reduced pressure, add water to the residue, and wash with ether. . The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. This extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting crystals are recrystallized from a mixture of ethyl acetate and n-hexane to obtain 2.10 g of N-[2,6-dichloro-4-(3-chlorophenoxy)phenyl]glycine ethyl ester. mpl07-10800. Elemental analysis: C, 4 days, BU03CI3 calculated value C48.51, day 2.91, N4.
04, CI30.69 experimental value C49.20, day 3.0
5, N3.93, CI28.78 Infrared absorption spectrum (Nujol method) maX arc-1: 3390, 1730 Nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 4.08 (ga, s) 5.
16 (IH, broad s) 6.83-7.50 (fine, m) Example 12 N-[4-(2-chlorophenoxy)phenyl]glycine ethyl ester 17.7 and N-chlorosuccinimide 17 Dissolve 80% of dioxane in 180% of dioxane,
Sham-frame for 1 hour at 0°C.

The reaction solution was added to 400ml of water and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. N-[2,6-dichloro-4-(
26.2 hours of the oily residue containing ethyl 2-chlorophenoxy)dalicine is dissolved in 20 parts of methanol. To this was added 100 ml of methanol solution containing 5.0 ml of sodium hydroxide, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with ether. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. When the obtained crystals are recrystallized from a mixture of ethyl acetate and n-hexane, N-[2
, 6-dichloro4-(2-chlorophenoxy)phenyl]glycine (7.0%) is obtained. mpl05~
106.5q○.

Elemental analysis: C, 4 days, bu03CI3 Calculated values C48.51, days 2.91, N4.04, CI
30.69 Experimental value C48.37, Day 2.75, N4.
09, CI29.85 Infrared absorption spectrum (Nujol method) maX skin-1: 3380, 1710 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 4.17 (2 days, s) 6.9
1 (ga, s) 7.0-7.67 (4 days, m) 7.83 (2 days, broad S) Example 13 N-(4-methoxyphenyl)glycine ethyl ester 15.0 m Dry benzene was dissolved in 100 ml of solution, and 20 ml of sulfuryl chloride was added dropwise to it at room temperature while stirring.

After the addition is completed, the mixture is heated at 50 qC for 1 hour, and after cooling, an aqueous solution of sodium bicarbonate is added to neutralize. The organic solvent layer is separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The oily residue containing N-(2,6-dichloro4-methoxyphenyl)glycine ethyl ester was dissolved in a methanol solution containing 10 parts of sodium hydroxide.
0 and leave it at room temperature overnight. Add one drop of water to this, wash with ether, acidify with concentrated hydrochloric acid, and extract with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting crystals are recrystallized from a solution of ethyl acetate and n-hexane to obtain 3.0 mL of white needle-like crystals of N-(2,6-dichloro-4-methoxyphenyl)glycine. mp143-14
y0.

Elemental analysis: C9 ratio N03CI2 Calculated value C43.22, day 3.63, N5.60 Experimental value C43.11, day 3.60, N5.63 Infrared absorption spectrum (Nujol method) -1:3380 of maXC
, 1740 Nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 3.75 (fine, s) 4.
00(,s) 7.01(2 days,s) Example 14 7.10% of N-(4-fluorophenyl)glycine and 14.0% of N-chlorosuccinimide were dissolved in dioxane 8%.
Dissolve in 0 qo and steep for 1 hour at 60 qo.

The reaction solution was cooled and poured into 300 mL of water, and the precipitated crystals were collected in an oven and air-dried. This was recrystallized from a solution of diisopropylene and n-hexane, and then further crystallized from ether and n-hexane.
Recrystallization from a mixture of -hexane gives 3.50 g of white columnar crystals of N-(2,6-dichloro-4-fluorophenyl)glycine. mp142-14500. Elemental analysis: C8 ratio N02CI2F Calculated value C40.36, day 2.54, N5.88 Experimental value C40.35, day 2.49, N5.82 Infrared absorption spectrum (Nujol method) maX arc-1:3190,
1730 Nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 3.42 (2 days, s) 4
．． 25 (IH, broad s) 6.11 (crime, d, J
=6HZ) Example 15 '1'N-phenylglycine ethyl ester hydrochloride 1
0.80 g of dry benzene is suspended on 100 g of dry benzene.

20.3 hours of sulfuryl chloride was added dropwise to this at room temperature while stirring, and after the dropping was completed, it was heated to 6000°C for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The extract was washed twice with water, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The oily residue was left at room temperature, and the precipitated crystals were collected in a furnace and recrystallized from methanol to yield white needle-like crystals of N-(2,4,6-tric.lophenyl)glycine ethyl ester. Get the evening. mp39-40go0.

Infrared absorption spectrum (Nujol method) -1 of maXC: 3380,1750 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1,33 (crude, t, J = 6H
Z) 4.23 (2 days, s) 4.30 (2 days, q, J=6
Day 2) 4.90 (IH, broad s) 7.25 (phantom, s) '2) 8.0 ml of N-(2,4,6-trichlorophenyl)glycine ethyl ester obtained above was dissolved in methanol. 1
Add to 00 place.

To this was added 20 methanol solution containing 4.0 m of sodium hydroxide, and the mixture was stirred at room temperature for 1 hour. Add the reaction solution to 1 part water
The mixture was poured into a liquid solution, brought to pHI with concentrated hydrochloric acid, and extracted with ether. After washing the extract with water and drying with magnesium sulfate,
The solvent is distilled off under reduced pressure. The resulting crystals are mixed with ether and n
- When recrystallized from a mixture of hexane, N-(2,4,6
-Trichlorophenyl)glycine 6.0 times white needles are obtained. mp185-186℃. Elemental analysis: C8QN0
2CI3 Calculated value C37.75, day 2.37, N5.50 Experimental value C37.64, day 2.29, N5.49 Infrared absorption spectrum (Nujol method) maX-1:3380,
1740 Nuclear magnetic resonance absorption spectrum 6 [(CD3)2CO] ppm: 4.26 (ga, s) 5
．． 20 (IH, brcad s) 7.30 (2 days, s) 8.0 (IH, broad s) Example 16 ○) Hydrochloride of N-phenyl-2-phenylglycine ethyl ester 9.0 t and Sulfuryl chloride 13.
Add 50 liters of benzene to 50 liters of Z, heat gradually while stirring, and boil at 6,000 ℃ for 2.5 hours.

When the solvent was distilled off from the reaction solution under reduced pressure, an oily N-(2
,4,6-triclo. 10.502 of phenyl)-2-phenylglycine ethyl ester is obtained. Infrared absorption spectrum (liquid film method) ShimaX skin-1: 3350,1735 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1,20 (fine, t, J = 7 days 2) 4.26 (2 days, q , J=7HZ)5.50(IH
, broad s) 5.83 (IH, s) 7.3-7.5 (7 days, m) '2} N-(2,4,6-trichlorophenyl)-2-phenyl obtained above A methanol solution containing 9.0 g of glycine ethyl ester and 4.0 g of sodium hydroxide
Dissolves in 0'.

Add 1 cup of water to this and let it sit at room temperature for 1 hour. Pour the reaction mixture into 1 liter of water, acidify with concentrated hydrochloric acid, and extract with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. When the obtained crystals are recrystallized from a solution of n-hexane and ether, N-(2,4,
5.30 g of white prismatic crystals of 6-trichlorophenyl)-2-phenylglycine are obtained. mP179-18
000.

Elemental analysis: C, 4 days, 02CI3 Calculated values C50.86, 3.05 days, N4.24 Experimental values C50.95, 2.90 days, N4.19 Infrared absorption spectrum (Nujol method) maX skin-1 :3400,
1720 Nuclear magnetic resonance absorption spectrum 6 [(CD3)2CO] ppm: 5.82 (IH, s)
7.26-7.5 (7 days, m) Example 17 [1} 11.50 g of N-phenylalanine methyl ester hydrochloride is suspended in 80 g of benzene.

Sulfuriluk for this. Ride 27.0 yen while dripping at room temperature, and after the dripping is finished, let it light for 1 hour at 50 to 6,000 ℃. After cooling, the reaction solution was neutralized by adding sodium hydrogen carbonate, and extracted with ether 500%. Wash the extract with water,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 14.20 g of oily N-(2,4,6-trichlorophenyl)alanine ethyl ester. Infrared absorption spectrum (liquid film method) maX arc-1: 3380, 1740 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1,27 (pan, t, J = 7H
Z) 1.43 (2 days, d, J=6Hz) 4.23 (but,
q, J = 7HZ) 4.26 (IH, q, J = 6 days 2) 7.20 (2 days, s) ■ N-(2,4,6-trichlorophenyl)alanine ethyl obtained above 14.0 yen of ester was dissolved in 50 methanol solutions containing 4.0 yen of sodium hydroxide and incubated at room temperature for 1 hour.

The reaction solution was poured into 500ml of water, made acidic with concentrated hydrochloric acid, and extracted with water. The extract is washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. When the oily residue is left to stand and the precipitated crystals are recrystallized from a mixture of n-hexane and ether, N-(2,4,6-trichlorophenyl)
6.30 hours of colorless needle crystals of alanine are obtained.

Elemental analysis: C9&N02CI3 Calculated value C40.25, day 3.00, N5.22 Experimental value C40.3$ day 2.88, N5.23 Infrared absorption spectrum (Nujol method) maX skin-1:3400,1
710 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1.47 (So, d, J; 7H
Z) 4.60 (IH, q, J = 7HZ) 7.23 (but,
s) 8.17 (ga.broad s) Example 18 N-phenyl-2-methylalanine ethyl ester 12
．． Dissolve 0.0 ml in 50 ml of dry benzene.

To this, sulfuryl chloride 27.0% was added dropwise at room temperature, and after the addition was completed, the temperature was gradually raised to 60°C.
I worshiped flies for two hours. After cooling, an aqueous sodium hydrogen carbonate solution is added to the reaction mixture to neutralize it, and the organic layer is separated. After washing with water and drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The oily residue containing N-(2,4,6-trichlorophenyl)-2-methylalanine ethyl ester was dissolved in a methanol solution containing 8.0 g of sodium hydroxide.
Dissolve in 50 ml of water and incubate at room temperature for 2 hours. Pour the reaction solution into water and wash with ether. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The oily residue is purified by silica gel column chromatography eluting with chloroform to give white crystals. When this is recrystallized from a mixture of n-hexane and ether, 4.0 g of colorless crystals of N-(2,4.6-trichlorophenyl)-2-methylalanine are obtained. mp90℃.
Elemental analysis: C, Rainbow, State 02CI3 calculated value C42.51
, day 3.57, N4.96 experimental value C42.66, day 3
．． 48, N5.01 Infrared absorption spectrum (Nujol method) maX skin-1: 3400, 1710 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 1.50 (spots, s) 7.37
Example 19 12.0 kg of N-phenyl-8-alanine ethyl ester is dissolved in 100 kg of dry benzene.

To this, 27.0 g of sulcryl chloride was added dropwise at room temperature while using a pestle, and after the addition was completed, it was simulated at 50°C for 40 minutes. After wrapping, the reaction solution is neutralized by adding an aqueous sodium hydrogen carbonate solution, and the organic layer is separated. This is concentrated under reduced pressure to obtain an oily residue containing N-(2,4,6-trichlorophenyl)-8-alanine ethyl ester. 100 methanol solution containing 7.0 m of sodium hydroxide in this
Add '' and let it stand at room temperature for 1 hour. Pour the reaction solution into 1 liter of water and wash with ether. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting crystals are recrystallized from a mixture of n-hexane and ethyl acetate to obtain 6.50 kg of colorless prismatic crystals of N-(2,4,6-trichlorophenyl)-8-alanine. mp85
~86qC. Elemental analysis: C9 is N02CI3 Calculated value C40.25, day 3.00, N5.22 Experimental value C40.01, day 2.92, N5.23 Infrared absorption spectrum (Nujol method) maX-1:3390,
1710 Nuclear magnetic resonance absorption spectrum 6 (DMSO-I) ppm: 2.50 (2 days, t, J =
7Hz) 3.58 (2 days, t, J=7HZ) 5.00 (IH, broad s) 7.55 (2 days, s) Example 20 N-(2,3-dichlorophenyl) Green 2. 10 minutes and 1.4 hours of N-chlorosuccinimide were dissolved in 50 minutes of dioxane and 2 hours at 6000 degrees. At 80 oo, we crossed the ocean for another 30 minutes.

The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in ether. After washing with water and drying over magnesium sulfate, the solvent is removed under reduced pressure. When the obtained crystals are recrystallized from Tsuru liquid of ethyl acetate and n-hexane, N÷(2
, 3,6-trichlorophenyl)glycine are obtained. mp209-2100○(
Disassembly). Elemental analysis: C8 ratio N02CI3 Calculated value C37.75, day 2.38, N5.50 Experimental value C37.70, day 2.30, N5.54 Infrared absorption spectrum (Nujol method) maX skin-1:3500,
1725 Nuclear magnetic resonance absorption spectrum 6 (DMSO-broad) ppm: 4.08 (2 days, d, J =
4Hz) 6.05 (IH, t, J = 4HZ) 6.70, 7.48 (2 days, ABq, J: 7Hz) Example 21 '1) 2,6-dichloro-3-nitroformanilide 59.5 50.8% of bromoacetic acid ethyl ester and 42.0% of potassium carbonate were dissolved in dimethylformamide 18%.
In addition to 0', I will pray for 3 hours at 90qo.

After cooling, pour the reaction solution into 1 liter of water and dilute with 500 ml of ether.
Extract times. The extract is washed with water, dried over magnesium sulfate, and then the ether is distilled off under reduced pressure. The oily residue is crystallized by treatment with a loss solution of ether and n-hexane (3:1) to give a pale yellow N-formyl-N-(2,6-dichloro-3-nitrophenyl)glycine ethyl ester. Obtain 51.20 crystals. mp75-77q0. Infrared absorption spectrum (Nujol method) m arc-1:17
40,1680 Nuclear magnetic resonance absorption spectrum 6 (DMSO-also) ppm: 1.20 (fine, t, J = 7
Hz) 4.13 (1.2 days, q, J = 7 HZ) 4.16 (0. group, q, J = 7 HZ) 4.41 (1), s) 4,61 (0. fence, s ) 7.8 to 8.3 (2 days, ABq overlap, J = 8 Hz) 8.33 (0. group, s) 8.50 (0.4 day, s) '2} N-formyl obtained above N-(2,6-dichloro-3nitrophenyl)glycine ethyl ester 4
Add 2.3% of the mixture to a mixture of 200% of acetic acid and 250% of concentrated hydrochloric acid, and heat under reflux for 2 hours.

After mixing, the reaction solution was poured into 1.5 liters of water and extracted three times with 50 ml of ether. The extract is washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. 50% water to oily residue
After adding 0, add sodium hydrogen carbonate aqueous solution while stirring to adjust the pH to 4. The precipitated crystals are collected by furnace,
After washing with water and air drying, 28.8 g of pale yellow crystals of N-(2,6-dichloro-3nitrophenyl)glycine are obtained. Take this product. Recrystallization from loform gives the purified product as pale yellow, prismatic crystals. mpl15-11900.
Elemental analysis: C8 is N204CI2 calculated value C36.25
, Sun 2.28, NIO. 57, CI26.75 experimental value
C36.17, Sun 2.18, NIO. 41, CI26.
91 Infrared absorption spectrum (Nujol method)
1:3350,1720 Nuclear magnetic resonance absorption spectrum a (DMSO-&) ppm: 3.58 (but, d, J=4
HZ) 4.91 (IH, t, J = 4Hz) 6.16, 6.33 (2 days, AOSq, J^B = 4HZ
) Example 22 Production of raw material compounds: {1} 4-aminosalicylic acid 15.30 g and N-
29.0 mm of chlorosuccinimide was dissolved in 250 mm of dioxane and incubated at an internal temperature of 90° C. for 2 hours.

Pour the reaction solution into 700ml of water, collect the precipitated crystals in a furnace,
After washing with water and air-drying, 19.50 g of crystals of 4-amino-3,5-dichlorosalicylic acid were obtained. mp230°C (decomposition). Infrared absorption spectrum (Nujol method) Shim Pine Skin-1: 3500, 3400, 1640 Nuclear Magnetic Resonance Absorption Spectrum 6 (DMSO-d6) ppm: 7.5
8 (IH, s) 6.41 (2 days, broad s)'2
} 18.0 g of the 4-amino-3,5-dichlorosalicylic acid obtained above was dissolved in a mixture of 100 g of acetic acid and 50 g of concentrated hydrochloric acid, and heated under reflux for 1 hour.

The reaction solution was concentrated under reduced pressure, and the residue was neutralized with an aqueous sodium bicarbonate solution and extracted with ether. Wash the extract with water,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 12.10 crystals of 3-amino-2,4-dichlorophenol. When this product is recrystallized from a mixture of ether and n-hexane, white, prismatic crystals are obtained. mp85-870. Elemental analysis: C6 & NOC12 calculated value C40.48, day 2.83, N7.86 experimental value C
40.40, day 2.71, N7.76 Infrared absorption spectrum (Nujol method) m-like skin-1:3400,330
0 Nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 5,30 (ga, s) 7.
10, 6.36 (2 days, Muichi Bq, J^B = 8 days 2) 1
000(IH,S) {3} 15.0 ml of 3-amino-2,4-dichlorophenol obtained above and 12.0 ml of potassium carbonate are added to 200 ml of acetone and heated under a candle.

To this was added dropwise 11.0 g of dimethyl sulfuric acid, and the mixture was heated under reflux for 1 hour. After cooling, insoluble matter in the reaction solution is removed in an oven, and the solvent is removed from the oven solution under reduced pressure. The oily residue is dissolved in ether and the ether solution is washed successively with aqueous sodium hydroxide and water and then dried over magnesium sulfate. Ether was distilled off from this solution under reduced pressure to obtain 16.0 g of oily 3-methoxy-2,6-dichloroaniline.
Infrared absorption spectrum (liquid film method) Shim Keika-1: 3500, 3400, 1610 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 3.83 (
Fine, s) 4.17 (Illusion, s) 6.25, 7.06 (2 days, ABq, J = 10HZ) ■ Mix 80% acetic anhydride and 40% sulfuric acid under ice cooling, This mixture was heated at the same temperature for 10 minutes and at 60°C for 15 minutes, and then cooled to room temperature.

To this solution, 16.0 g of 3-methoxy-2,6-dichloroaniline obtained above was added at once, and the mixture was allowed to stand at room temperature for 1 hour. The reaction mixture is poured into cold water, and the precipitated crystals are collected in a furnace and washed with water. When this is recrystallized from ethanol, 3
13.50 hours of white needle-like crystals of -methoxy-2,6-dichloroformanilide are obtained. mp157-15800.

Infrared absorption spectrum (Nujol method) Shim C-1: 3250, 1660 Nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 3.88 (3 days, s) 7
．． 11, 7.51 (2 days, ABq, J = 10 Hz) 8.30 (IH, s) Production of target compound: {1} Sodium hydride 2.3 days dried benzene 50
Suspend it on the ground, hang it on a rope for 5 minutes, and then remove the liquid using the head fishing method.

Add 200 g of benzene to the residue, and add 11.0 g of 2,6-dichloro-3-toxyformanilide while stirring. In addition, dimethylformamide 2
After dripping the mixture at room temperature, the temperature was gradually raised in an oil bath and heated under reflux for 1 hour. After cooling this to an internal temperature of 20 qo, promacetic acid ethyl ester 9.0
A benzene solution containing 30 ml of water was added while dripping.
After the dropwise addition is completed, the mixture is heated under reflux for 1 hour. After mixing, water is added to the reaction solution and the organic layer is separated. After washing with water and drying with magnesium sulfate, the solvent was removed under reduced pressure to obtain 14.0 g of oily N-formyl-N-(2,6-dichloro-3-methoxyphenyl)glycine ethyl ester. . Infrared absorption spectrum (liquid film method) Shim Matsuga-1: 1760, 1750 (shoulder), 1700 nuclear magnetic resonance absorption spectrum 6 (DMSO-wide) ppm: 1
．． 16 (lees, t, J = 7 Hz) 3.91 (fine, s) 4,09 (1, 3, q, J dry 7 Hz) 4.15 (0.67 days, q, J = 7 Hz) 4.33 (1.39 days, s) 4.46 (0.67 days, s) 7.16-7.70 (crime, ABq overlap, J=9Hz) 8.21 (0.67 days, s ) 8.43 (o. 39 days, s) ■ N-formyl-N-(2,6-dichloro-
3-methoxyphenyl)glycine ethyl ester 12.
Dissolve 0.0% in a mixture of 60% acetic acid and 20% concentrated hydrochloric acid, and
．． Immediately heat to reflux.

After cooling, the solvent is distilled off from the reaction solution under reduced pressure, and the oily residue is dissolved in ether. After washing the ether solution with water and drying with magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained crystals were mixed with a mixture of ethyl acetate and n-hexane (2:
Recrystallization from 1) gives 2.40 g of white crystals of N-(2,6-dichloro-3-methoxyphenyl)glycine. mpl09~1100○. Elemental analysis: C9 ratio N03
CI2 calculated value C43.22, day, 3.63N5.60
Experimental value C43.31, day 3.57, N5.67 Infrared absorption spectrum (Nujol method) m arc-1:340
0,1725 Nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 3.81 (spots, s) 4.
18 (spots, s) 5.12 (IH, broad s) 6.65 7.25 (2 days, ABq, J=6HZ) Example 23 '11 Sodium hydride 2.40 yen and dried benzene 2
Suspend at 0'.

Remove the benzene by squeezing it and add 200ml of benzene to the remaining groove. To this, 15.0 g of 2,6-dimethyl-3-(2-chlorobenzoyl)acetanilide was added, and then 2 g of dimethylformamide was added while stirring, and the mixture was gradually heated to reflux for 30 minutes. . After this was allowed to cool, a solution of 8.40 parts of ethyl bromoacetate and 20 parts of benzene was added dropwise thereto, and after the dropwise addition was completed, the mixture was heated under reflux for 30 minutes. After mixing, pour the reaction solution into water and separate the organic layer. After washing with water and drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The pale yellow, oily residue was purified by silica gel column chromatography and eluted with chloroform to give an oily N-acetyl-N-[3-(
15.50 kg of 2-chlorobenzoyl)-2,6-kylycylglycine ethyl ester are obtained. Infrared absorption spectrum (Nujol method) mpine skin-1:1760,166
0-1680 nuclear magnetic resonance absorption spectrum 6 (CDC13
) ppm: 1.28 (2 days, t, J=7HZ) 1.81
(3rd, s) 2.40 (group, S) 2,43 (crime, s) 4.17 (2nd, S) 4.20 (2nd, q, J=7HZ) 7, 2~7, 41 (fine, m) '2' 15.0% of the N-acetyl-N-[3-(2-chlorobenzoyl)-2,6-chilycyl]glycine ethyl ester obtained above was mixed with 15% sulfuric acid 100M and acetic acid 40%. Dissolve the solution in a mixed solution of water and heat under reflux at a room temperature of 150 pm for 1 hour.

The reaction mixture is poured into 400ml of water, added with sodium bicarbonate powder to pH 4 and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The oily residue is crystallized by treatment with benzene and enamel solution, n-hexane is added thereto, and the crystals are filtered out. When this is recrystallized from a mixture of ethanol and ethyl acetate, N-acetyl-N-[3-(
7.0 g of white prismatic crystals of 2-chlorobenzoyl)-2,6-xylyl]glycine are obtained. mp161-162
0. Infrared absorption spectrum (Nujol method) of pine skin
1:1755, 1660, 1620 nuclear magnetic resonance absorption spectrum 8 (DMSO-d6) ppm: 1.86 (9 days,
s) 2.44 (9 days, S) 2.48 (net, s) 4.08 (bait, s) 7.28-7.64 (fence, m) '3' N-acetyl- obtained above N-[3-(2-chlorobenzoyl)-2,6-xylyl]glycine 7.0
Dissolve 50% sulfuric acid in 100ml of sulfuric acid and boil at ambient temperature of 18°C.
Heat to reflux for an hour.

The reaction solution was poured into 300ml of water, the pH was adjusted to 4 by adding sodium bicarbonate, and the mixture was extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The oily residue was left to stand, the precipitated crystals were collected in a furnace, and recrystallized from a mixture of ethyl acetate and n-hexane for 4 hours.
When repeated, N-[3-(2-chlorobenzoyl)-
2.10 prismatic crystals of 2,6-xylyl]glycine are obtained. mpl08-109q○. Elemental analysis: C, 7 days,
6N03CI Calculated value C64.25, day 5.07, N4.41 Experimental value C64.32, day 5.02, N4.44 Infrared absorption spectrum (Nujol method) Himi-like skin-1:3400,1
730,160 nuclear magnetic resonance absorption spectrum 6 (DMSO
-d6) ppm: 2,40 (fine, s) 2,45 (fine, s
) 3.80 (2 days, s) 6.76, 7.03 (2 days, ABq, J:8HZ) 7.43-7.66 (calm, m) Example 24 2,6-dichloroacetanilide 5. Suspend the solution in 50M dry benzene.

Add 1.20 g of sodium hydride to this and heat under reflux for 40 minutes. After cooling, 15 parts of a benzene solution of 5.0 parts of ethyl bromoacetate was added dropwise at room temperature.
Heat to reflux for an hour. Water is added to the reaction mixture and the organic layer is separated. After washing with water and drying over magnesium sulfate, the solvent is distilled off under reduced pressure. N-acetyl N-(2
, 6-dichlorophenyl) glycine ethyl ester. Oily residue6.0 Sodium hydroxide4.
Add 5 ml of methanol solution containing 0 ml, and add 2 ml of methanol solution containing 40 ml.
Time to worship the Nada. Add 500M water to the reaction mixture and wash with ether. This aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting oily residue was allowed to stand, and the precipitated crystals were collected in a furnace and recrystallized from a mixture of n-hexane and ether to yield white crystals of N-acetyl-N-(2,6-dichlorophenyl)glycine 4. ．．
Get 10 evenings. mp134-135qo. Elemental analysis: C
, Phantom 9N03CI2 calculated value C45.80, day 3.43
, N5.34 experimental value C45.91, day 3.41, N5
．． 32 Infrared absorption spectrum (Nujol method) m Isohada-1: 1730, 1680 Nuclear magnetic resonance absorption spectrum 6 (DCCl3) ppm: 1.93 (pan, s) 4.26
(2 days, s) 7.15-7.60 (group, m) 11.20 (IH, s) Example 25 10.209 of 2,6-dichloroacetanilide was suspended in 100 g of dry benzene, and hydrogen was added to this. Sodium chloride 12
．． After adding 40 minutes at room temperature while stirring, the mixture was heated under reflux for 1 hour.

A benzene solution of 8.0 g of y-furomobutyronitrile was added dropwise to this at room temperature, and after the dropwise addition was completed, the mixture was heated under reflux for 1 hour.
After cooling, the reaction solution was poured into water overnight and extracted with ether. The solvent was removed from the extract under reduced pressure, and the residue was diluted with 100% concentrated hydrochloric acid.
Add him. After heating and refluxing this for 4 hours, the solvent was removed under reduced pressure. The residue is dissolved in aqueous sodium hydroxide solution and washed with ether. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ether. After washing the extract with water and drying over magnesium sulfate, the solvent is removed under reduced pressure. The obtained crystals were recrystallized from a flowing solution of ether and n-hexane,
Further, recrystallization from a filtrate of ethyl acetate and n-hexane yields N-acetyl-N-(2,6-dichlorophenyl).
4.60 kg of butyric acid needles are obtained. mp125-126℃
. Elemental analysis: C, 2 days, 3N03CI2 calculated value C49
．． 67, day 4.52, N4.82 experimental value C49.37
, day 4.40, N4.81 infrared absorption spectrum (Nujol method) m desk-1: 1740, 1630 nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 1.67 (9 days, s) 1
．． 50-2.33 (4 days, m) 3.47-3.71 (ga, m) 7.38-7.78 (crude, m) Example 26 Drying 2,6-dichloroacetanilide 10.20 m Suspended in 100 parts of toluene, and added 2 parts of sodium hydride to this.
．． After adding 88 liters of water at room temperature, gradually overflow and leave 10,000 ml of water for 1 hour.

After leaving it to cool, 5.40 g of chloracetonitrile was added dropwise, and after the dropping was completed, it was heated to 100 ml for 1 hour.
Add 500ml of water to the reaction solution and extract with 300ml of ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and an oily residue of 8.70% was obtained from the penzene eluate. When this was treated with a slurry of ether and n-hexane to crystallize, white crystals of N-cyanomethyl-2,6-dichloroacetanilide 7.5%
Get 0 nights. mp49-5000. Infrared absorption spectrum (Nujol method) Shim Uriga-1:1690 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1.19 (ga, s) 4.55
(Bait, s) 7.20 to 7.60 (3 days, m) Example 27 Production of raw material compounds: '1) Potassium salt of 3-amino-2,4-dichlorophenol 21.0 m, frombenzene 20 m Add 3.0 ml of active oxidized steel to 100 ml of dimethylformamide and heat under reflux for 1 hour while stirring.

After cooling, insoluble matter in the reaction solution is removed from the oven, and enamel is added to the solution, followed by washing with water. After drying the ether solution over magnesium sulfate, the solvent is removed under reduced pressure. The dark brown, oily residue was subjected to silica gel column chromatography.
Elute with a concentrated solution of benzene and n-hexane (1:1).
Fractions containing the desired compound were collected and the solvent was removed under reduced pressure to yield colorless, oily 3-phenoxy 2,6
-8.20 g of dichloroaniline was obtained. Infrared absorption spectrum (liquid film method) Shim Isohada-1: 3500, 3400, 1610 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 4.70 (
2nd, bmad S) 6.25-7.50 (7th, m)
'2} Mix 60 parts of acetic anhydride and 30 parts of acidic acid under ice cooling, heat at the same temperature for 5 minutes and at 6000 °C for 18 minutes, and then cool to room temperature.

To this solution was added 8.0 g of 3-phenoxy-2,6-dichloroaniline obtained above, and the mixture was left overnight at room temperature. The reaction solution is poured into water, and the precipitated crystals are collected in a furnace and washed with water.
This was subjected to silica gel column chromatography,
Elution is carried out with chloroform, and the solvent is distilled off from the eluate under reduced pressure to obtain white crystals. When this is recrystallized from methanol, 5.50 g of white needle-like crystals of 3-phenoxy-2,6-dichloroformanidine are obtained. mp142~1
4y0.

Elemental analysis: C, 3 days 9N02CI2 Calculated values C55.34, days 3.22, N4.96 Experimental values C55.45, days 3.25, N4.95 Infrared absorption spectrum (Nujol method) m-1: 3200,1
660 Nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 6.90-7.40 (7
Day, m) 8.32 (IH, s) 10.12 (IH, s) Production of target compound: '1) Suspend 0.90 g of sodium hydride (purity 60%) in 20 g of dry benzene, Pray for 5 minutes.

The mixture is depleted of benzene and 100 cm of fresh benzene is added to the residue. To this, the 3-
After adding 5.0 g of phenoxy-2,6-dichloroformanilide and further adding 2 g of dimethylformamide, the temperature was gradually raised while stirring, and the mixture was heated under reflux for 1 hour. After cooling this to room temperature, a solution of 3.0 g of ethyl promethacetate and 10 g of benzene was added dropwise thereto. After completion of the dropwise addition, the mixture was heated under reflux for 1 hour. After cooling, the reaction solution was poured into water and extracted with 200 ml of ether. The extract was washed with water and dried over magnesium sulfate, and the solvent was removed under reduced pressure to yield colorless, oily N-formyl-N-(3-phenoxy-2,6-dichlorophenyl)glycine ethyl ester 6.0 Infrared absorption spectrum (liquid film method) Shim Toku-1: 1750, 1690 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 1.26 (9 days, t, J = 8
Day 2) 4.16 (o.9th, q, J=8HZ) 4.20
(1.7 days, q, J=8HZ) 6.80-7.50 (7 days, m) 8.20 (0.1 spots, s) 8.40 (o.8 spots, s) {2} Add 6.0 parts of N-formyl-N-(3-phenoxy-2,6-dichlorophenyl)glycine ethyl ester obtained above to 50 parts of acetic acid and 10 parts of concentrated hydrochloric acid, ．． Heat to reflux for an hour.

The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The dendritic residue is subjected to silica gel column chromatography, eluting with benzene and ethyl acetate solution (5:3). Fractions containing the desired compound are collected and the solvent is removed under reduced pressure to obtain crystals. When this is recrystallized from a mixture of n-hexane and ethyl acetate, white crystals of N-(3-phenoxy-2,6-dichlorophenyl)glycine 2.
Get 0 nights. mpl07-108q0. Elemental analysis: C,
4th day... N03CI2 Calculated value C53.87, day 3.55, N4.48 Experimental value C54.03, day 3.54, N4.55 Infrared absorption spectrum (Nujol method) m magnetic skin-1:3380,1
705 Nuclear magnetic resonance absorption spectrum 6 (DMSO- also) ppm: 4.23 (2 days, d, J =
7HZ) 5.50 (IH, t, J = 7HZ) 6.36-7.50 (7 days, m) Example 28 [1} N-[4-(N-acetylanilino)phenyl]glycinethyl Add 5.50 g of hydrochloride of ester to an aqueous sodium bicarbonate solution and extract with ether.

The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure to obtain oily N-[4-(N-acetylanilino)phenyl]glycine ethyl ester. This oil was dissolved in 50 parts of dioxane, 4.6 parts of N-chlorosuccinimide was added thereto, and 60 parts of dioxane was added thereto.
2 at °C. Worship the insect time hawk. After cooling, the solvent was removed from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ether. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5.0 g of oily N-[2,6-dichloro4-(N-acetylanilino)phenyl]glycine ethyl ester. Infrared absorption spectrum (
Liquid film method) Shim Isohada-1: 3400, 1740, 1670 nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 1.28 (
3 days, t, J = 7 days 2) 2.04 (crime, s) 4.16 (
2 days, S) 4.24 (2 days, q, J = 7 days 2) 7.04-7.60 (7 days, m) {2' N-[2,6-dichloro4- (N
5.0 g of glycine ethyl ester was dissolved in 50 g of an ethanol solution containing 3.0 g of potassium hydroxide, and heated under reflux for 1 hour.

The reaction solution is concentrated under reduced pressure, water is added to the residue, and the residue is washed with ether. The aqueous solution was brought to pH 2 with concentrated hydrochloric acid and extracted with ether. The extract is washed with saturated aqueous sodium chloride solution, treated with activated carbon, dried over magnesium sulfate and then the solvent is distilled off under reduced pressure. The residue was dissolved in ethyl acetate and n
- When recrystallized from a solution of hexane, N-(2,6-dichloro-4-anilinophenyl)glycine crystals 1.7
Get 0 nights. mP130-132 ``0.

Elemental analysis: C, 4 days, 2N202CI2 Calculated value C54.04, Day 3.89, N9.00 Experimental value C53.77, Day 3.89, N8.80 Infrared absorption spectrum (Nujol method) -1 of m :3410,3
380,1720 Nuclear Magnetic Resonance Absorption Spectrum 6 (DMS
O-d6) ppm: 3.93 (IH, s) 6.67-7
．． 41 (7 days, m) 8.10 (IH, s) Example 29 [1} 27.70 parts of N-(2,6-dichloro-3-nitrophenyl)glycine, 150 parts of dry ethanol containing 1 part of sulfuric acid and heat under reflux for 2 hours.

The solvent was distilled off from the reaction solution under reduced pressure, and the residue was neutralized by adding an aqueous solution of sodium hydrogen carbonate, followed by extraction with ether. The extract was washed twice with 100 parts of water, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue is recrystallized from ethanol to give 25.80 g of crystals of N-(2,6-dichloro-3nitophenyl)glycine ethyl ester. mP54.5-56.500
.

Infrared absorption spectrum (Nujol method) Shimachihada-1:3350,1750 Nuclear magnetic resonance absorption spectrum 6 (DMSO-also) ppm: 1.20 (Chihichi, t, J=
7HZ) 4.12 (2 days, q, J = 7HZ) 4.36 (2 days, d, J = 7HZ) 6.00 (IH, t, J = 7 days 2) 7.40, 7.60 ( 2 days, ABq, J = 10 Hz) {21 1.0 ml of N-(2,6-dichloro-3-nitrophenyl)glycine ethyl ester obtained above was dissolved in 50 ml of ethyl acetate, and 10% palladium on carbon was added to this.
．． Add 1 night for contact reduction.

The reaction ends when the hydrogen gas 230' is absorbed, and the catalyst in the reaction solution is removed from the furnace. The solvent is distilled off from the furnace liquid under reduced pressure, and ethanol-hydrochloric acid and ether are added to the residue.
When the precipitated crystals are collected in a furnace and recrystallized from a mixture of ethanol and ether, needle-like crystals of N-(2,6-dichloro-3-aminophenyl)glycine ethyl ester hydrochloride are obtained.
．． Get 35 evenings. mP144-15800 (degraded).

Elemental analysis: C, Rainbow, 3N202CI3 Calculated values C40.09, 4.37 days, N9.35 Experimental values C39.91, 4.35 days, N9.56 Infrared absorption spectrum (Nujol method) m Isoka-1: 3380,1
755 Nuclear magnetic resonance absorption spectrum 6 (DMSO- also) ppm: 1.16 (9 days, t, J =
7Hz) 4.10 (ga, q, J = 7HZ) 4,24 (spot, s) 6.84, 7.24 (crime, ABq, J = 8 days 2) Lake N- obtained as above (2,6-dichloro-3
-aminophenyl) glycine ethyl ester hydrochloride 5
．． Dissolve 0 ml in 50 ml of methanol.

To this was added 30 g of a methanol solution containing 3.7 g of potassium hydroxide, and the mixture was allowed to stand at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and 100 parts of water was added to the residue, which was then washed twice with ether. Adjust the aqueous solution to approximately pH with concentrated hydrochloric acid.
3 and extracted twice with 150 g of ether. The extract is washed with water and dried over magnesium sulfate, and then the cabbage is removed under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give N-(2,6-dichloro3
2.6 hours of white crystals of -amino/phenyl)glycine are obtained. mpl12-11yC.

Elemental analysis: C8 is N202CI2 calculated value C40.87, day 3.43, NIl. 92 Experimental value C40.98, day 3.45N12.11 infrared absorption spectrum (Nujol method) m skin skin-1:3360,
2200-2800,1600 nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 4.08 (Sawa, s) 5
．． 50 (2nd, broad s) 6.33, 6.91 (
2 days, ABq, J = 10 days 2) '4' 4.8 days of N-(2,6-dichloro-3-aminophenyl)glycine and 2.6 days of pendyl chloride obtained as above were added to 100 days of ethanol. and water 50'
After adding 2.80 g of potassium carbonate to this solution, it was incubated for 2 hours at an internal temperature of 50 oo.

The solvent was distilled off from the reaction solution under reduced pressure, and a 5% aqueous potassium hydroxide solution was added to the residue to adjust the pH to 12. After washing this with ether, the pH is adjusted to about 4 with 10% hydrochloric acid. This is extracted with ether, the extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The oily residue was subjected to silica gel column chromatography.
Elute with chloroform. The fractions containing the target compound are collected and the solvent is removed under reduced pressure. When the crystals taken are recrystallized from a mixture of n-hexane and ethyl acetate,
1.20 g of white crystals of N-(2,6-dichloro-3-pendylaminophenyl)glycine are obtained. mPIII
~113q○.

Elemental analysis: C, 5 days, 4N2CI2 Calculated values C55.40, 4.34 days, N8.61 Experimental values C55.81, 4.36 days, N8.51 Infrared absorption spectrum (Nujol method) m-skin-1 :3480,1
770,1630 nuclear magnetic resonance absorption spectrum 6 (CDC
13) ppm: 3.70 (2 days, s) 4.40 (but, s
) 5.38 (ga, o) 6.56, 7.00 (2 days, ABq, J=10Hz) 7.20-7.40 (spots, m) Example 30 Example 29-{1},' 2} obtained in the same manner as N-(2
, 6-dichloro-3-aminophenyl) glycine ethyl ester hydrochloride (3.50 g) and 3.4-dimethoxybenzoyl chloride (2.69 g) in dry pyridine (40 g).
Dissolve in water and incubate at room temperature for 2 hours.

Add 100 parts of water to the reaction solution, and extract twice with 100 parts of ethyl acetate. The extracts are combined, washed twice with water, dried over magnesium sulfate, and then the solvent is removed under reduced pressure. The residue was recrystallized from 30% ethanol to give N-[2
, 6-dichloro-3-(3,4-dimethoxybenzamido)phenyl]glycine ethyl ester 4.0 times a day are obtained. mpl18.5-12000.

Elemental analysis: C, Niji 2bu 205CI2 Calculated values C53.41, 4.72, N6.56 Experimental values C53.34, 4.65, N6.49 Infrared absorption spectrum (Nujol method) m Pine skin-1 :3450,3
350, 1750, 1670 nuclear magnetic resonance absorption spectrum 6 (DMSO- also) ppm: 1.20 (3 days, t, J =
7Hz) 3.84 (bait, s) 4.10 (group, q, J = 7HZ) 4.24 (ga, d, J: 7HZ) 5.44 (IH, t, 1 = 8HZ) 7.0~ 7.70 (Square, m) 9.80 (IH, s) ■ N-[2,6-dichloro-3-(3,4
-Dimethoxybenzamido)phenyl]glycine ethyl ester 2.50 μm was added to 20 μm of a methanol solution of 1.20 μm of sodium hydroxide, and after stirring at room temperature,
Add 100 parts of methanol and 10 parts of water to this, and stir at room temperature for 2 hours.

The solvent was distilled off from the reaction solution under reduced pressure, and 200 g of water was added to the residue, which was washed with ethyl acetate. The aqueous solution was adjusted to pH 3-4 with 10% hydrochloric acid, the precipitated crystals were collected in a furnace, and recrystallized from ethanol.
, 4-dimethoxybenzamido)phenyl]glycine. 1.20 g of white crystals are obtained. mp231-23 Mori○. Elemental analysis: C, 7 days, 205CI2 calculated value 051.1
4, Day 4.04, N7.02 Experimental values C51.37, Day 3.99, N6.98 Infrared absorption spectrum (Nujol method) m arc-1:3300,1755 Nuclear magnetic resonance absorption spectrum 6 (DMSO- d6) ppm: 3.82 (fine, s) 4.
16 (2 days, s) 7.00-7.70 (group, m) 9.80 (IH, s) Example 31 '1} N-(4-benzylphenyl) glycine ethyl ester 10.5 days and N-chlorosuccinimide 1
Add 100% dioxane to 100% dioxane and add 100% dioxane at internal temperature 6000.
．． The light is on for 5 hours.

Dioxane was distilled off from the reaction solution under reduced pressure, and 1 part of water was added to the residue.
Add 00' and extract over ether 200. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the ether was removed under reduced pressure to yield oily N-(2,6-dichloro-4-pendylphenyl)glycine ethyl ester '12.3. get. Infrared absorption spectrum (NaCI film method)
1:3400,1750 Nuclear Magnetic Resonance Absorption Spectrum 6 (CCl4) ppm: 1,23 (Team, t, J = 6H
Z) 3.77 (ga, s) 4.17 (ga, q, J=6HZ
) 6.9-7.4 (7 days, m) {2) 12 days of N-(2,6-dichloro-4-pendylphenyl)glycine ethyl ester obtained above and 7.5 days of sodium hydroxide were added. Add 150 g of water and heat under reflux for 1 hour.

After the reaction solution is allowed to cool, it is washed with Febre 150 cloth. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with 150 m' of ether.
The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the ether is removed under reduced pressure. The oily residue is dissolved in 30 ml of saturated aqueous sodium bicarbonate solution. This solution was washed twice with 20 parts of ethyl acetate, and then layered with ether. This is made acidic with 10% hydrochloric acid, and the ether layer is separated. This ether solution is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the ether is removed under reduced pressure. The oily residue is dissolved in a mixture of 30 parts of ethanol and 3 parts of water, and 350 parts of sodium acetate is added thereto and dissolved by heating. Remove the lacquer from the furnace and leave the furnace solution at room temperature. When the precipitate is collected in a furnace and washed with a small amount of cold ethanol, N-(2,6
-Dichloro-4-pendylphenyl)glycine sodium (0.8 kg) was obtained as pale yellowish brown crystals. mP217-219
00.

Elemental analysis: C, 5 days. 2N02C! 2Na calculated value C5
3.27, day 3.77, N4.14 experimental value C52.8
2, 3.90 days, 3.94 days, 201.49 days infrared absorption spectrum (NaC1, Nujol method)
:3400,1600 Nuclear magnetic resonance absorption spectrum 6 (DMSO-d6) ppm: 3.58 (2 days, s) 3
．． 80 (2 days, s) 5.75 (IH, broad s) 7.1 to 7.4 (7 days, m) Example 32 Same as Example 29-{1}, '2), '3} A mixture of 1.0 g of N-(3-amino-2,6-dichlorophenylglycine, 0.68 g of benzyl chloride and 1.17 g of potassium carbonate prepared in The mixture was dissolved in water and heated under reflux for 1.5 hours.

To this was added 1.08 g of penzyl chloride and 1.18 g of potassium carbonate, and the mixture was heated under reflux for 2 hours. The solvent was distilled off from the reaction solution under reduced pressure, 100 g of water was added to the residue, and the mixture was washed with ether. The aqueous solution is acidified with 10% hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate, treated with activated carbon, and then the ether is distilled off under reduced pressure. The oily residue was purified by silica gel column chromatography to yield N-[2,6-dichloro. -3-(N,N-dibenzylamino)phenyl]
Obtain 0.15 g of glycine crystals. mpl05~107
0. Elemental analysis: C22nd, Bu202CI2 calculated value C6
3.62, day 4.85, N6.75 experimental value C63.8
2, day 4.84, N6.84 infrared absorption spectrum (Nujol method) Machihada-1:3200,1690 Nuclear magnetic resonance absorption spectrum 6 (CDCWppm: 3.90 (ga, s) 4.26 (2
days, s) 4.40 (ga, s) 6.50, 7.12 (2 days, ABq, J=8Hz) 7.20-7.50 (10 days, m) Example 33 N-(2-ethyl phenyl ) Glycine ethyl ester 7
．． 90°C and 14.9°C of N-bromosuccinimide are dissolved in 50°C of dioxane and heated at 450°C for 2 hours.

Dioxane was removed from the reaction solution under reduced pressure, and 5% of water was added to the remaining water.
Add 00 fence and extract with ether. Wash the extract with water,
After drying with magnesium sulfate, the solvent is distilled off under reduced pressure. The oily residue was dissolved in 50 parts of methanol and mixed with a methanol solution containing 8.0 parts of potassium hydroxide.
Add 0 and leave for 1 hour at room temperature. Methanol was removed from the reaction solution under reduced pressure, and 300 g of water was added to the residue.
Wash with 100% of ether. Adjust the aqueous solution to pH with concentrated hydrochloric acid.
I and extracted with ether. After washing the extract with water and drying with magnesium sulfate, ether was added to the crab under reduced pressure.
leave The residue was recrystallized twice from a solution of n-hexane and ethyl acetate to obtain 2.80 g of white crystals of N-(2-ethyl-4,6-dibromophenyl)glycine. m
pl16-118.500. Elemental analysis: C, rainbow,. N0
2Br2 calculated value C35.63, day 3.29, N4.2
6 Experimental values C35.56 days 3.19, N4.34 Infrared absorption spectrum (Nujol method) M-like skin - 1:335
0,1720 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1,20 (group, t, J = 7H
Z) 2.66 (2 days, q, Jヱ7HZ) 3.93 (2 days, s) 6.80 (crime, s) 7.23 (IH, d, J = 2 days 2) 7.46 ( IH, d, J = 2 days 2) Example 34 '1' N-Chlorosuccinimide 17.7 minutes, add dioxane 100°C and warm to 60°C.

After adding 17.4 g of N-[4-(3-fluorophenoxy)phenyl]glycine ethyl ester little by little, the mixture was heated for 1 hour at an internal temperature of 55 qo. After dioxane was distilled off from the reaction solution under reduced pressure, 200% of water was added to the residue.
Add. This was extracted twice with 150 parts of ether, and the extract was washed twice with 100 parts of a 5% aqueous sodium chloride solution, dried over magnesium sulfate, and the ether was removed under reduced pressure to form an oily N-[2] , 6-dichloro 41 (
21.1 of 3-fluorophenoxy)phenylglycine ethyl ester was obtained. Infrared absorption spectrum (liquid film method) ShimaX skin-1: 3400, 1745 Nuclear magnetic resonance absorption spectrum 6 (CCl4) ppm: 1.30 (crime, t, J = 7 days 2) 3.70 (2 days, s ) 3.89 (spotted, q, J = 7 days 2) 4.74 (IH, d) 6.6-7.4 (fine, m) ■ N-[2,6-dichloro-4- (3-Fluorophenoxy)phenyl]glycine ethyl ester (21.0 mm) was dissolved in 100 mm of methanol.

To this was added 100 g of a methanol solution containing 16.5 g of potassium hydroxide, and the mixture was stirred at room temperature for 2 hours. Methanol is distilled off from the reaction solution under reduced pressure, and 200 ml of water is added to the residue to dissolve it. This was washed twice with 100% of ether, acidified with concentrated hydrochloric acid, and extracted twice with 200% of ether. The extract was washed with a 5% aqueous sodium chloride solution, dried over magnesium sulfate, the ether was removed under reduced pressure, and the resulting crystals were recrystallized from a mixture of ethyl acetate and n-hexane (1:2). As a result, 15.1 crystals of N-[2,6-dichloro4-(3fluorophenoxy)phenyl]glycine are obtained. mplll0~111.5
00.

Elemental analysis: C, 4 days, 03CI2 calculated value C50.93 days 3.05, N4.24 experimental value
C50.88, Sun 3.05, N. 4.27 Infrared absorption spectrum (Nujol method) maX skin-1:3380,
1730 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 4,00 (spots, s) 6.80
~7.20 (fine, m) 7.25 (IH, d) Example 35 {1' 3.8 g of 2-furomopyridine are dissolved in 50 g of dry dimethylformamide.

To this were added 6.9 tb of sodium salt of N-(2,6-dichloro-4-hydroxyphenyl)glycinethyl ester and 0.8 tb of cupric oxide. ．． Insect Kagoma Touma Azusa. Add the reaction solution to 200ml of water,
Extract twice with 150 ml of ether. The extract is washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the ether is distilled off under reduced pressure. Obtained oil 5.
After purification by subjecting the sample to silica gel column chromatography and eluting with benzene, an oily N
-[2,6-dichloro4-(2-pyridyloxy)phenyl]glycine ethyl ester 1.0 ml is obtained. Infrared absorption spectrum (liquid film method) maX skin-1:3400
, 1750 Nuclear magnetic resonance absorption spectrum 8 (CDC13) ppm: 1.28 (spot, t, J: 7H
Z) 4.15 (2 days, s) 4.25 (2 days, q, J=7
HZ) 4.75 (IH, s) 6-7 to 8.3 (Mother's Day, m) '2) N-[2,6-dichloro-4-(2
-pyridyloxy)phenyl]glycine ethyl ester 1.0 peach is melted.

To this was added 10 parts of a methanol solution in which 1.0 parts of potassium hydroxide was dissolved, and the mixture was allowed to stand at room temperature for 2 hours. Methanol was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in 30 cm of water. Wash this with ether and add 10% hydrochloric acid to pH 2.
After that, extract twice with 50 ml of ether. After washing the extract with water and drying over magnesium sulfate, the ether is distilled off under reduced pressure. Obtained oil 1. M was dissolved in 30% of a saturated aqueous solution of sodium bicarbonate, washed with ether, acidified with 10% hydrochloric acid, and dissolved in 30% of ether.
Extract twice. The extract was washed with water, dried over magnesium sulfate, and then the ether was removed under reduced pressure, resulting in N-[
1.0 crystals of 2,6-dichloro4-(2-pyridyloxy)phenyl]glycine were obtained. This product is recrystallized from a mixed solution of ethyl acetate and n-hexane to obtain a purified product. mP146-149d○.

Elemental analysis: C, 3rd, state 203CI2 Calculated value C49.86, day 3.22, N8.95 Experimental value C49.66, day 3.12, N8.95 Infrared absorption spectrum (Nujol method) maX arc-1 :3390,
3100,1725 Nuclear Magnetic Resonance Absorption Spectrum 6 (DM
SO-d6) ppm: 4.07 (ga, s) 5.09 (I
H, s) 7.0-8.10 (fine, m) Example 36 {11 N-[4-(3,5-xylyloxy)phenyl] glycine ethyl ester 31.89 and N-chlorosuccinimide 31.2 In the evening, add 200 dioxane to me, and worship at 6000 for 1 hour and 20 minutes.

The solvent was removed from the reaction solution under reduced pressure, 300 g of water was added to the residue, and the mixture was extracted with 200 g of ether and then with 100 g of ether. The extract was washed with 100 liters of water, dried over magnesium sulfate, and the ether was distilled off under reduced pressure to obtain oily N-[2,6-dichloro-4-(3,5-xylyloxy)phenyl]glycine ethyl. ester 4
Get 1.3 evenings. Infrared absorption spectrum (film, N
aCI) ma
Hz) 2.26 (pot, s) 4.08 (2 days, s) 4.24 (2 days, q, J = 7 days 2) 4.44 (IH, broad s) 6.4-7.0 (QH,m) '2} N-[2,6-dichloro-4-(3
,5-xylyloxy)phenyl]41 parts of glycine ethyl ester and 10 parts of sodium hydroxide were added to 200 parts of methanol, 1. Worship the insects on a rope.

Methanol was distilled off from the reaction solution under reduced pressure, and 30 methanol was added to the remaining bay.
0 Dissolve on the desk. This was washed with 150 parts of ether, made acidic with concentrated hydrochloric acid, and then extracted with 300 parts of Ebru. The extract was washed with 100ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the ether was removed under reduced pressure. When the residual bamboo is crystallized by treating it with a mixture of benzene and n-hexane, N-[2,6-dichloro-4
19.7 crystals of mono(3,5-xylyloxy)phenyl]bricine were obtained. mP124-127C.

Elemental analysis: C, 6 days, 5N03CI2 Calculated value C56.48, Day 4.44, N4.12 Experimental value C56.22, Day 4.42, N4.12 Infrared absorption spectrum (Nujol method) maxcm-1:3400
, 1720 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 225 (group, s) 4.10 (
2 days, s) 6.5-7.0 (porridge, m) 7.75 (2 days, broad s) Example 37 N-[4-(2,5-xylyloxy)phenyl] glycine ethyl ester 12.3 s) and add 12.1 μl of N-chlorosuccinimide to dioxane.
Worship the hawk for 1.5 hours at 50-60o○.

Dioxane was distilled off from the reaction solution under reduced pressure, and 15% of water was added to the residue.
After adding 100 g of ether, extract twice with 100 g each of ether. The extract was washed with 50 volumes of water and then with 50 volumes of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the ether was distilled off under reduced pressure to give an oily N-[2,
15.5 grams of 6-dichloro4-(2,5-xylyloxy)phenylglycine ethyl ester are obtained. Infrared absorption spectrum (liquid film method) -1 of maXC: 3400,1750 Nuclear magnetic resonance absorption spectrum 6 (CC14)) ppm: 1.28 (3 days, t, J = 7
HZ) 2.15 (3 days, s) 2.28 (hi, s) 4.00 (ga, s) 4.20 (2 days, q, J = 7 days 2) 4.45 (IH, broad s) ) 6.50 to 7.15 (spots, m) ■ N-[2,6-dichloro4-(2,5
-xylyloxy)phenyl]15 parts of glycine ethyl ester and 3 parts of potassium hydroxide were added to 60 parts of methanol, and the mixture was heated under reflux for 2 hours.

Methanol was distilled off from the reaction solution under reduced pressure, and 20% of water was added to the remaining sugar.
Add and dissolve. This is ether for each loo'
After washing twice with
00 I extract it twice. The extract was washed with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the ether was distilled off under reduced pressure. The residual liquid is mixed with benzene and n-
Treatment with a trickle of hexane gives 3.9 g of N-[2,6-dichloro-4-(2,5-xylyloxy)phenyl]glycine. The solvent is distilled off from the mother liquor under reduced pressure, and the residue is dissolved in a saturated aqueous solution of sodium bicarbonate and cooled.
The precipitated crystals (sodium salt) are collected in a furnace and dissolved in water,
After acidifying with concentrated hydrochloric acid, extract with ether. After washing this extract with water and drying over magnesium sulfate, the ether was distilled off under reduced pressure to obtain the desired product 4.7. This is combined with the previously obtained target product 3.9 and recrystallized from a solution of benzene and n-hexane to obtain the purified product 6.9. mp73-75qo.

Elemental analysis: C, 6 days, 5N03CI2 Calculated values C56.48, 4.44 days, N4.12 Experimental values C56.13, 4.42 days, N4.07 Infrared absorption spectrum (Nujol method) maXC 1: 3400
, 1725 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 2.16 (crude, s) 2.32
(3 days, s) 4-2〇2 days, S) 6.65-7.40 (SH, m) 7.05 (2 days, broad s,) Example 38 {1) N-[4- (2-Fluorophenoxy)phenylglycine ethyl ester 15.4 and N-chlorosuccinimide 15.

Add 100% of didioxane to 50 to 6000
The light will be lit for 2 hours.

Dioxane was removed from the reaction solution under reduced pressure, and 10% of water was added to the residue.
Add 0' and extract with ether 80 I and then with 40 ether. Wash the extract with 100% water,
After drying with magnesium sulfate, the ether was removed under reduced pressure to obtain an oily N-[2,6-dichloro4-(2)
-Fluorophenoxy)phenyl]glycine ethyl ester 20 times was obtained. Infrared absorption spectrum (liquid film method) ShimaX skin-1: 3400, 1750 Nuclear magnetic resonance absorption spectrum 6 (CCl4) ppm: 1.28 (spots, t, J = 7 days 2
) 4.00 (2 days, s) 4.20 (4 days, q, J=7H
Z) 4.50 (IH, broad s) 6.83 to 7.32 (fine, m) ■ N-[2,6-dichloro4-(2-fluorophenoxy)phenyl]glycinethyl obtained above ester 209% and potassium hydroxide 4.7% methanol 60%
Add to this and heat under reflux for 1 hour.

Methanol was distilled off from the reaction solution under reduced pressure, and the residue was mixed with 10% water.
Dissolves in 0'. Wash this with 100 yen,
After making acidic with concentrated hydrochloric acid, extract with 100 ml of ether and then 50 ml of ether. The extract was washed with 50 g of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the ether was removed under reduced pressure. The oily residue is heated and dissolved in 100% of a saturated aqueous solution of sodium bicarbonate, and then cooled. The precipitated sodium salt is collected in a furnace, dissolved in water, acidified with hydrochloric acid, and then extracted with ether 200 and then ether 100. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the ether was distilled off under reduced pressure.
Obtains an oily residue. When this is crystallized from a mixture of benzene and n-hexane, N-[2,6-dichloro4-(
2-Fluorophenoxy)phenyl glycine crystals 1
Get one evening. mpl05-10700.

Elemental analysis: C, 4 days, bu03CI2F Calculated values C50.93, days 3.05, N4.24 Experimental values C51.11, days 3.08, N4.30 Infrared absorption spectrum (Nujol method) maX-1 :3400,
1730 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 4.15 (ga, s) 6.85
~7.35 (Tsumugi, m) 7.88 (2nd, broad s
〉 Example 39 10 units of N-[4-(2,4-xylyloxy)phenyl]glycine ethyl ester and 9.85 units of N-chlorosuccinimide were added to 100 units of dioxane, and 50 to
60qo and 1. Worshiping insect time.

Dioxane was distilled off from the reaction solution under reduced pressure, and 10% of water was added to the residue.
Add 0 above, ether 150 secretion, then ether 50
Extract with. The extract was dissolved in a saturated sodium chloride aqueous solution 5
After washing with 0M and drying with magnesium sulfate, the ether was distilled off under reduced pressure to obtain oily N-[2,6-dichloro4-(2,4.xylyloxy)phenyl]glycine ethyl ester 14.2 Get the evening. Infrared absorption spectrum (liquid film method) maX skin-1: 3400, 1750 Nuclear magnetic resonance absorption spectrum 8 (CC14)) ppm: 1.28 (crime, t, J = 7H
Z) 2.15 (spots, s) 2.30 (slims, s) 4.00 (2 days, s) 4.20 (2 days, q, J=7Hz) 6.70-7.10 (spots, m) {2} N-[2,6-dichloro-4-(2
, 4-xylyloxy)phenyl]glycine ethyl ester and 3 parts of potassium hydroxide were mixed with 60 parts of methanol.
Add to '' and heat under reflux for 1 hour.

Methanol was distilled off from the reaction solution under reduced pressure, and the residue was mixed with 10% water.
After dissolving the solution, wash with 100% ether. This is acidified with hydrochloric acid and extracted with 150 parts of ether and then with 50 parts of ether. The extract was washed with 50 g of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the ether was distilled off under reduced pressure. The oily residue was heated and dissolved in 100 g of a saturated aqueous solution of sodium bicarbonate, and then left in a cool place overnight. The precipitated sodium salt is collected in an oven, dissolved in 100 ml of water, acidified with hydrochloric acid, and then extracted with ether. The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the ether is distilled off under reduced pressure. When the oily residue is crystallized from a benzene and n-hexane solution, N-[2,6-dichloro-4-
7.1 crystals of (2,4-xylyloxy)phenyl]glycine were obtained. mp134-13600.

Elemental analysis: C, 6 days, 5NQC12 calculated value C56.48 days 4.44, N4.12 experimental value
C56.36, day 4.41, N4.05 infrared absorption spectrum (Nujol method) maX-1:3400,1
730 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 2.12 (SH, s) 2.2
9 (lees, s) 4.06 (ga, s) 6.8-7.1 (ban, m) 7.52 (ga, broad s) Example 40 (1) N-[4-(3,4 -xylyloxy)phenyl]10 glycine ethyl ester and 9.85 g of N-chlorosuccinimide are added to 100 g of dioxane and heated at 50-6000 g for 1.5 hours.

Dioxane was distilled off from the reaction solution under reduced pressure, and 10% of water was added to the residue.
Add 0 similar, ether 100', then ether 50
Extract with skin. The extract was dissolved in a saturated aqueous solution of sodium chloride.
After washing with water and drying with magnesium sulfate, the ether was removed under reduced pressure to obtain oily N-[2,6-dichloro-4-(3,4-xylyloxy)phenyl]-glycine ethyl ester 12.1 Get the evening. Infrared absorption spectrum (liquid film method) -1 of maXC: 3400,1750 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 1.27 (g, t, J: 7 days 2) 2.20 (fine, s) 4.04 (2 days, s) 4.21 (4 days, q, J=7HZ) 4.40 (IH, broad s) 6.60-7.15 (mother, m) (2' obtained above N-[2,6-dichloro-4-(3,
12 parts of 4-xylyloxy)phenyl glycine ethyl ester and 2.6 parts of potassium hydroxide were added to 5 parts of methanol.
0 and heated under reflux for 1 hour.

Methanol is removed from the reaction solution under reduced pressure, and the resulting residue (potassium salt) is pulverized with a 100% saturated aqueous solution of sodium chloride, and the precipitate is heated in a furnace. Add this to ether 150 [
After washing with water and dissolving in 150ml of water and making acidic with hydrochloric acid, it is extracted with 150ml of ether and then with 50ml of ether. The extract was washed with 50 g of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the ale was removed under reduced pressure. When the thin layer is crystallized from a liquid solution of benzene and n-hexane, 5.9 times of crystals of N-[2,6-dichloro-4-(3,4-xylyloxy)phenyl]glycine are obtained. Similarly, 1.3 times of the target substance was obtained from the mother liquor. Total yield 7.2 mpl12-110. Elemental analysis: C, 6 days,
5NQC12 Calculated value C56.48 days 4,44, N4.12 Experimental value
C56.72, day 4.44, N4.14 infrared absorption spectrum (Nujol method) maX fence-1:3400,1
725 Nuclear magnetic resonance absorption spectrum 6 (CDCl3) ppm: 2,25 (fine, s) 4.10
(2 days, s) 6.58-7.20 (spots, m) 7.72 (2 days, broad s) Example 41 2-Chlorobenzothiazole 3.3 minutes of dried dimethylformamide and N-[ Add 5.0 ml of sodium salt of 2,6-dichloro-4-hydroxyphenylglycine ethyl ester, and adjust to 1.0 ml at 100 ml. Worship the insect time hawk.

The reaction solution was added to 250 ml of water and diluted with 150 ml of ether.
Extract times. After washing the extract with water and drying over magnesium sulfate, the ether is removed under reduced pressure. 6.9 ml of the obtained oil was dissolved in 50 ml of methanol, a methanol solution containing 5.0 ml of potassium hydroxide was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol is distilled off from this reaction solution under reduced pressure, and after adding 15 parts of water to the residue, the pH is adjusted to about 2 with 10% hydrochloric acid. This was extracted twice with 200 g of ether, the extract was washed with water, dried over magnesium sulfate, and then the ether was distilled off under reduced pressure. The oily residue was dissolved in 20 parts of a saturated aqueous solution of sodium bicarbonate, and 2 parts of a saturated aqueous solution of sodium chloride were added to this solution, followed by cooling on ice. The precipitated crystals were collected in a furnace, washed with ether, Recrystallization from a mixture of ethanol and water (8:1) yields N-[
2.8% of the sodium salt of 2,6-dichloro4-(2-penzothiazolyloxy)phenylglycine is obtained.
mp226-231℃. Elemental analysis: C, 6 days 9N203
SC12Na calculation value C46.05, day 2.32, N7
．． 16 Experimental values C43.18, Day 2.79, N6.64
, day 206.18 infrared absorption spectrum (Nujol method) maX arc-1: 3390, 1675, 1605 nuclear magnetic resonance absorption spectrum 6 (DMSO-&) ppm: 3.
45 (spot, d, J = 4HZ) 6.00 (but, t, J = 4
HZ) 7,15-7,95 (fine, m) Example 42 (1) N-[4-(3,4,5-trimethylphenylene/xy)phenyl] glycine ethyl ester 6.5% and N-chlorosuccinimide 6. Add 60 ml of dioxane for 2 hours and let it cool for 1 hour at an internal temperature of 50-6000.

Dioxane was distilled off from the reaction solution under reduced pressure, and 10% of water was added to the residue.
After adding 0 skin, extract with 100' of ether, then 50' of ether. The extract was washed twice with water, dried over magnesium sulfate, and the ether was distilled off under reduced pressure to obtain an oily N-[2,6-dichloro-4-(3,4,5
-trimethylphenoxy)phenyl]glycine ethyl ester is obtained. Infrared absorption spectrum (liquid film method) maXC selection 1: 3400, 1750 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 1.27 (3 days, t, J = 7
HZ) 2.13 (so, s) 2.25 (thin, s) 4.08 (2 days, s) 4.23 (2 days, q, J; 7 days 2) 6.63 (2 days, s ) 6.90(,s) '21 N-[2,6-dichloro-4-(3,
8.7 g of 4,5-trimethylphenoxy)phenylglycine ethyl ester and 1.9 g of potassium hydroxide are added to 50 g of methanol and heated under reflux for 1 hour.

Methanol was removed from the reaction solution under reduced pressure, and the residue was dissolved in water.
After heating and dissolving the mixture, cool it. The precipitated crystals (potassium salt) are collected in a furnace and mixed with a small amount of water and 50% of ether.
After washing sequentially with water, suspend it in 50ml of water. A thin layer of 100% ether was added to this, acidified with concentrated hydrochloric acid, and the ether layer was separated. The aqueous layer is extracted with 50% of ether, and the extract is combined with the previously separated ether solution. After washing with water and drying over magnesium sulfate, the ether is removed under reduced pressure. When the resulting residue is crystallized by treating it with a mixture of benzene and n-hexane, yellowish brown crystals of N-[2,6-dichloro4-(3,4,5-trimethylphenoxy)phenyl]glycine are obtained. Get the evening. mp1
40-14g○. Elemental analysis: C, 7 days, 7NQC12 Calculated values C57.64, Days 4.84, N3.96 Experimental values C58.35, Days 4.81, N3.98 Infrared absorption spectrum (Nujol method) maX - 1:3400,
1720 Nuclear magnetic resonance absorption spectrum 6 (CDC13) ppm: 212 (9th, s) 221 (
Spot, s) 4.09 (ga, s) 6.61 (2 days, s) 6.90 (ga, s) 7.79 (2 days, broad s)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ Alkyl group, lower alkoxy group, phenoxy group, anilino group, N-acetylanilino group, benzyl group, mono- or dibenzylamino group,
A benzoyl group optionally substituted with halogen, a lower alkoxy-substituted benzoylamino group, a tetrazolyl group, a benzothiazolyl group, a benzothiazolyloxy group, or a pyridyloxy group, R_4 is a hydrogen atom or a lower alkanoyl group, R_5 is a lower alkylene group or Each means a phenylmethylene group, and the phenoxy group of R_6 may be substituted with a halogen atom, a halo-lower alkyl group, or a lower alkyl group, and when R_3 is a hydrogen atom, R_4 is a lower alkanoyl group. ) N-substituted phenylamino fatty acids, their salts, and derivatives at the carboxy group selected from nitriles, amides and lower alkyl esters.