JPS6032756A - Production of n-(cis-3,4-dimethoxycinnamoyl)-anthranylic acid - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as an antiallergic agent, in high yield, by reacting anhydrous cis-3,4-dimethoxycinnamoyl carbonic acid monoester with an anthranylic acid compound. CONSTITUTION:The objective compound of formula III is prepared by reacting the anhydrous cis-3,4-dimethoxycinnamoyl carbonic acid monoester of formula I (R is univalent hydrocarbon group) with the anthranylic acid compound of formula II (Z is H or carboxyl-protecting group) in an organic solvent such as THF at <= room temperature. EFFECT:The isomerization from cis to trans can be prevented by the reaction via the mixed acid anhydride using a chlorocarbonic acid ester.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing anthranilic acid derivatives, and more specifically, in the following formula, Z represents a water purple atom or a carboxyl protecting group. The present invention relates to a novel method for producing somethoxycinnamoyl)anthranilic acid compound.

N-(tran, s-3,4-somethoxy), which is represented by the following formula, has recently attracted attention as an orally administrable anti-allergic agent.

The present inventors synthesized tranilast to study the pharmacological activity of tranilast (trans isomer) represented by the above formula, stored it in a solution state in the laboratory, and found that its pharmacological activity changed over time. I found a strange phenomenon called
As a result of investigating the cause, we found that tranilast (trans isomer)
is a compound represented by the above formula (1) when irradiated with light causes a photochemical reaction and Z represents a hydrogen atom, that is, N-(ois-3,4-somethoxycinnamoyl)anthranilic acid ( Hereinafter [referred to as cis-compound-1] is cow 1
I discovered that iK could be used and proposed it first (patent application 1983).
-179976).

As is clear from the in vitro and in vivo tests described below, the tendency for this cis form is more than 10 times that of trans form tranilast when sacrificed in vitro, and 18 to 10 times or more when tested in vivo. As mentioned above, tranilast has extremely excellent anti-allergic effects that were completely unexpected from the effects of tranilast, and it is effective against bronchial asthma, hives 4, atopic dermatitis, and allergy 5. - It is considered to be extremely useful as an antiallergic agent such as a treatment for rhinitis.

On the other hand, methods for producing a series of anthranilic acid derivatives including the above-mentioned tranilast are disclosed in Japanese Patent Publication No. 56-40710,
Japanese Patent Publication No. 57-36905, Japanese Patent Publication No. 50-1404
Publication No. 13, Japanese Patent Publication No. 56-48504, Japanese Patent Publication No. 56-48504
2-83428, JP 52-83429, JP 52-83473, JP 52-65279
No. 4, Japanese Patent Publication No. 17186/1986, and if one typical method is used, tranilast is a reactive, functionally efficient derivative of 3,4-somethoxycinnamic acid represented by the following formula. 41i is produced by reacting anthyl 9-chloric acid with the following formula. The above-mentioned reactive functional derivatives of 3.4-dimethoxycinnamic acid include acid halides, acid anhydrides, mixed acid anhydrides, esters, and N,
Adducts with N'-direduced carbodiimide, etc. are described.

Therefore, the present inventors attempted to produce the above-mentioned cis-form compound, which is even more active than tranilast, by the above-mentioned method, but the starting material, cis-3,4-dimethoxycinnamic acid, i.e. 3゜4-Somethoxyallocinnamic acid is a very unstable compound, and it is difficult to convert this adduct into a reactive functional derivative as described above and/or successfully convert it into a reactive functional derivative. Even if it were possible, during the subsequent reaction with anthranyl+i&, cis → trans isomerization occurs in most cases,
The target cis compound could not be obtained. For example, a method using an acid chloride as the reactive functional derivative isomerizes cis-3,4-somethoxylinocinnamic acid to a salt-deprived nitrosinnamic acid such as thionyl chloride. Also,
Oxychlorination+4 method considered to be via a mixed acid anhydride with sochlorophosphoric acid as a method for the middization of reactive functional derivatives of cis-3,4-dimethoxyallocinnamic acid and anthranilic acid; symmetrical acid anhydride When using the benzenesulfonyl chloride method, which is believed to be via .

It was discovered that the desired cis-form compound could be produced in a uniform yield without causing the desired N-(C1m-3,4-somethoxylation, and the present invention was completed.

Therefore, according to the present invention, anhydrous aim-3,4-dimethoxycinnamic acid carbonate monoester represented by the formula Ill in which R represents a monovalent hydrocarbon group, where Z is Representing a hydrogen atom or a carboxyl protecting group, in the formula, Z has the above meaning, N-(cis-3,4-somethoxycinnamate represented by A method for producing a moyl)anthranilic acid compound is provided.

In the above formula (Ill), "one hydrocarbon" represented by R is an arbitrary hydrocarbon that is usually used as an ester residue of chlorocarbonate in the field of peptide synthesis by the mixed acid anhydride method. It can be a hydrocarbon residue, including lower alkyl groups such as methyl, ethyl 〇-thyl, isobutyl, and 5ea-butyl; aralkyl groups such as Penzl's; and rearyl groups such as phenyl. Among these, lower alkyl groups, particularly ethyl and isobutyl groups, are preferred.

In addition, in the above formula (mill), the [carboxyl protecting group I] represented by Z is, for example, methyl,
Ethyl, n-propyl, 1so-propyl, n-butyl, 80-butyl, 5ea-butyl, tart-
Examples include lower alkyl groups such as butyl; aralkyl groups such as pensol; tetrahydropyranyl, and salt-forming cations such as sodium and potassium.

In this specification, the term "lower" means that the number of carbon atoms in the compound or group to which this term is attached is 6 or less, preferably 4 or less.

The reaction between the mixed acid anhydride of the formula (ml) and the anthranilic acid compound of the formula (Ill) is usually carried out in an organic solvent, but it can also be carried out in a mixed solvent of an organic solvent and water. Examples of solvents include ethers such as tetrahydrofuran and sooxane; chlorinated hydrocarbons such as methylene chloride and chloroform; hydrocarbons such as benzene and toluene; ketones such as cetone, methyl ethyl ketone, and t; esters such as ethyl acetate. Class: Dimethylformamide (DMF), Dimethylsulfoxide (DNS
Among them, tetrahydrofuran, benzene, acetone, etc. are preferably used.

In order to avoid isomerization of cia-+ trans, it is desirable to use as gentle a reaction temperature as possible, and usually room temperature or lower temperature is used, but in some cases temperatures up to about 120°C are used. You can use this heating condition.

The ratio of the anthranilic acid mixture of the formula (m) to the mixed acid anhydride of the formula (m) is not strictly limited and can be varied over a wide range; On the other hand, the compound of formula (+D) is 1.0 to 1
．． It is convenient to use within the range of 5 mol, preferably within the range of 1.1 to 1.2 mol.

Although the above reaction proceeds smoothly without the presence of a radical, for example, when using a free carboxylic acid as the compound of t (III), if necessary, water and organic It can also be carried out in a mixed solvent with a solvent. Such bases include $ tertiary organic amines such as triethylamine and diisopropylamine; sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,
Examples include inorganic bases such as sodium hydroxide and potassium hydroxide.

11- The amount of base used is 1Fl, and the compound 1 of the formula (1111)
Within the range of 1.0 to 1.5 equivalents per mole, preferably 1.0 to 1.5 equivalents per mole.
It is convenient to use the appetizer in the range of 1 to 1.2 equivalents.

The above reaction can be completed in about 6 to 30 hours, more generally about 15 to 20 hours, under the conditions as described above.

After the reaction, the resulting compound of formula (1) can be processed by methods known per se, such as extraction, chromatography, recrystallization,
Separation from the reaction mixture and/or fW41! can do.

If the compound of formula CI)ty> in which Z represents a carboxyl protecting group thus obtained, the group Z is
When the hydrogen atom is replaced by T, the compound of the formula (6, which can be changed to the compound of 11 or its salt, for example, the formula Fl where Z is a lower alkyl group) has -14- 1.5 to 1O equivalent cis → trαn8 by reacting for 15 to 90 minutes, preferably at 60 to 120°C, preferably at 65 to 95°C, using an alcoholic sodium hydroxide aqueous solution of 5 to 1 g equivalent, preferably for about 60 minutes.
can be hydrolyzed without isomerization.

The mixed acid anhydride of the formula (Ill) used as a starting material in the above-described method is prepared according to a method known per se to prepare cig-3,4-dimethoxycinnamic acid (3
. It can be produced by reacting at the following temperatures.

The reaction between the compound of formula (IV) and the chlorocarbonate of formula (V) can generally be carried out in an inert solvent. As the solvent, the same organic solvents as those mentioned above for the reaction of the mixed acid anhydride of the formula [1] and the anthranyl-containing compound of the formula (11) can be exemplified, and among them, tetrahydrofuran, acetone, etc. , benzene and the like are preferred.

The above reaction can be carried out at a relatively low temperature, and the reaction temperature can be varied depending on the type of chlorocarbonate used, but is generally within the range of 5°C to about room temperature, preferably O'C. Temperatures in the range ˜25° C. are suitable.

The ratio of the chlorocarbonate of formula (Vl) to the compound of formula (M) is not critical and can be varied over a wide range, but is usually 11 mols of the chlorocarbonate of formula (V) per 61 moles of the compound of formula (1/). Examples of the vine base in the range of .0 to 1.5 mol, preferably 1.1 to 1.2 mol include tertiary organic amines such as triethylamine, tri-n-butylamine, and soisoderobylamine; carbonic acid; Examples include inorganic bases such as sodium, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and triethylamine, of which triethylamine is preferred. These bases are usually compounds of the formula (In). Within the range of i, o to 1.5 moles per 11 moles, preferably 1.1
It can be used on dragons within the range of ~1 or 2 dragons.

Alternatively, the above reaction can be carried out by using a compound of the formula (Ml) in the form of a salt. Such salts include -17-, for example, alkali metal salts such as sodium salts and potassium salts; ammonium salts, etc. Can be mentioned.

The mixed acid anhydride of day c can be separated from the reaction mixture and/or prepared by methods known per se, for example by means of extraction, washing, chromatography, etc.

Alternatively, without isolating the mixed acid anhydride of formula (1'), the above compound of formula (II/) and formula IVIIJIZ)
It may be carried out in a one-pot process by continuing the reaction of the chlorocarbonic ester, the thus obtained mixed acid anhydride of formula (厘), and the reaction of the γ-notradylic acid compound of formula (11).

The compound of the formula (1) provided by the method of the present invention, especially the compound of the formula where Z represents a hydrogen atom, that is, the cis compound, has excellent anti-allergy properties as described above. It has an effect,
It is considered to be extremely useful as an antiallergic agent for treating bronchial asthma, urticaria, dermatitis, and 71/Lugian rhinitis.

The excellent antiallergic activity of the cis compound can be demonstrated by the in vitro and in vivo preparations described below.

(1) In vitro V@Soil [Method] A male Wistar rat weighing 250 g was exsanguinated to death by decapitation, and the animal was placed in a Tyrode-gel solution (110 mJ containing 110 mJ/110 mJ/100 mJ/incubation with a Tyrode-gel solution). After injecting the abdomen for about 2 minutes, the abdomen was opened and the intraperitoneal cell fluid was collected.The collected intraperitoneal cell fluid was diluted to 100% G.
, centrifuge at 4℃ for 3 minutes, add suitable water-cooled phosphate buffer to the sediment, wash 3 times, and prepare 1 old order, separate package number of 5 to 10.
The suspension solution was prepared so that the ratio was 1000 ml/me. This suspension contained about 25% hypertrophy.

The sputum to be sputum contains N-(cis-3,4-somethoxycinnamoyl)anthranilic acid [cis compound*] and N
-(trans-3,4-somethoxycinnamoyl)anthranilic acid [tranilast], 1% N when used.
It was dissolved in an aqueous solution of αHCO, diluted as necessary, and used in experiments.

Add 0.3- of the test drug solution to the above rat intraperitoneal cell suspension Z5-, and incubate for 1 minute at 37°C.
1'48/80 0.2ttll/ml) and further incubated for 20 minutes.

Stop the reaction with water cooling + hL centrifugation protection, May et al.
Histamine was extracted by the method of Allttrg, 46: 12.1970), and the strawberry release and residual histamine were measured using a fluorophotometer (Hitachi model 101 model).

[Results] The results are shown in Table 1 below. As is clear from Table 1,
cis compound, N-(aim-3,4-J methoxycinnamoyl)anthranilic acid ha, lo.

048/80 inhibited histamine release from rat hypertrophic cells by 15% at μI/ml/## degrees, and 500a
85% inhibition at i/1d4kK and 95% inhibition at logo#, 9/di degrees; on the other hand, tranilast, which is a trans form, showed substantial inhibition at drug concentrations of 100 to i, o o o μt/-. It can be seen that there is no effect on suppressing histamine release.

-21- [Method] Male Hartley guinea pigs weighing 200 to 300 g were sensitized by injecting half the amount of the antigen ovalbumin 2 owg/motor/- into the -22- 1F muscle and intraperitoneal cavity.
1 day and 5 days later, sensitization was carried out in the same manner. 4 weeks after final sensitization,
The guinea pigs were sacrificed by exsanguination, the ileum was removed, and the removed ileum was cut into pieces of 1.5 to 2 L-m in length.
Co, =95:5, suspended in Tyrode's solution (10-) to examine the influence on the SD reaction.

1ttll constant Ha, 10-',? The ratio of the contraction height due to 5ylO-' g/mt antigen to the contraction height due to histamine (Xl) and the ratio (Y) in the presence of the test drug was determined in the same manner, and the inhibition rate (%) was calculated as (1-Y /X)-100 yielded 9. The test drug was also orally injected 5 minutes before antigen application.

High contraction of antigen and high contraction of histamine in the presence of test drug [Results] Table 2 below shows the results of the test drug department for the SD reaction using isolated guinea pigs 4 weeks after sensitization.

As is clear from Table 2, N-(cis-3
,4-dimethoxycinnamoyl)anthramylic acid ij,
10-' and H I O-'I/- (25-30% in concentration
1O-41! /m1d4 degrees is 84.5
%, 10-s In 97ml concentration 3, the SD reaction was 100
%, but on the other hand, the inhibitory effect of tranilast is much weaker than that of N-(via-3,4-dimethoxycinnamoyl)anthranilic acid even at one time [sigma] drug.

2nd; &: 5chultz-Da of guinea pig extraction fluency
Inhibitory effect on la reaction -25- [Method] Normal human blood and blood from patients with myeloid leukemia were used. Blood was collected by adding 30~so1 position/- to the blood, and 6% dextran saline was added with a fingernail.
．． 1 mol ED T, A Ki Station. In addition to full pressure elbow straightening l〈
The mixture was mixed thoroughly and allowed to stand at room temperature for 1 hour to precipitate red blood cells, and the upper layer of plasma containing white blood cells was collected into a plastic centrifuge tube. This plasma was centrifuged at room temperature for 8 minutes (37sG
ll, Tris-A-EDTA was added to the obtained precipitate,
(i(Tris 3.03g/l, NaCL 7.O
11//l, KCI G, 371177% pH'i
, 6. Containing 0.03% human lupulmin and 1 mole of EDTAαO) was added in an appropriate amount, stirred gently to suspend, and centrifuged for 8 minutes at room temperature.

The obtained precipitate was treated with Trim-A-EDTA buffer and Tris-ACM buffer (rris 2oai/), N
αC17,0,111/I, KCI α3711/1-
26- CaC1, 2H, 00,09N/l, MgC1゜6H
, OQ, 2 a 5 y/l, Human Alpumi 70.03
% containing) were washed once each day. After counting the number of white blood cells, add 5×1O・cells per test tube, 8 ml.
It was adjusted to be a T r i & ACM laxative solution.

To determine the release of 5H5-A from a white 1 m sphere, place 5 x 10' packets in a plastic test tube and add Ca-1no-p.
hore A-231st 2.5pil/Q,, 1t
t4 was added and reacted at 37°C for 20 minutes. 5Rs of drugs
The 5-A release inhibitory effect is caused by Ca-1nophora A-
Before addition of 23187, 0.1- of drug #IJ solution of each concentration was added, and the reaction was carried out at 37° C. for 40 minutes. After the reaction was completed, it was cooled with water, 41 ml of ethanol was added, and -
Stored at 20°C. , 5 RS-A was measured using Hartley male guinea pig ileum. The ileum of the guinea pig was removed, cut into 2 to 31 pieces, and placed in a Magnus bath (30±0.5°C, O: CO,
=95:5, suspended in 5 dl of l'yrode solution, 5
X 10-' molar concentration of atropine sulfate and I
The contraction height caused by mepyramine 84 at a 10-molar concentration was measured, and the contraction height caused by histamine 5n9/- was defined as SR5-A activity 1 unit/-, and the drug.
The inhibitory effect on S-, f release was expressed as the ratio of the 5R5-A activity released from drug-treated leukocytes to the 5R5-A activity released from untreated leukocytes.

[Conclusion] (a) Leukocytes from normal human white fluid Table 3 shows the inhibitory effects of drugs on SR5-Al4 dissociation from leukocytes from normal human blood samples. As is clear from Table 3, 5. The 5M5-A aJm inhibition rate of V-(cis-3,4-dimethoxycinnamoyl)anthranilic acid is IX10-'-v-ru skin! LI'+d32%,
1'10-''MoA' (mg 64% j?j heel ylo-4 molar concentration was 69%.

On the other hand, the 5R5-A release inhibition rate of tranilast, which is a control group, was 15% for 10-a molar aif and 1xto-
'molar concentration 38% and txio-' molar, inertia 44%
Met. Thus, even at different drug concentrations, 7V-(cis-3,4-dimethoxycinnamoyl)anthranilic acid was found to have a stronger 5R5-Aa dissociation inhibitory effect than tranilast. .

-29- 5R5-Al from leukocytes derived from bone and leukemia patient blood
Table 4 shows the inhibitory effect of drugs on 1-fi.
As is clear from the 5R
5-A play! The inhibitory effect on normal human leukocytes and co-workers showed that it had a stronger SRS-A Jj female inhibitory effect than tranilast even in the degree of drug suppression.

Table 4 5R5-A from leukocytes from myeloid leukemia patients
Inhibitory effect on release (2) In vivo test effect [Method] For SD male and female rats weighing approximately 200 g, ovalbumin lη/, ribs in both large ++; intrameat injection (5 m
//kglt,, at the same time 1fnt C8 cough vaccine (2
x10 pieces Bordetalla pertusai
s/-) was administered intraperitoneally for sensitization. After 12 days, blood was collected and antiserum was obtained. 48 hour honolog of this antiserum
oua PCA titer was l:32. Weight 250
The above antiserum diluted 10 times with physiological saline was subcutaneously injected into the shaved back of male and female SD rats weighing ~300 g across the midline of % IE at 0.1 increments at 3 locations. As a control, physiological saline αl- was subcutaneously injected into three other locations.

After 48 hours, 05% Evans blue l- containing 2 kg of ovalbumin was injected into the tail vein to induce a PCA reaction.

3. After 0 minutes, exsanguinate, cut out the dye leakage site, and
atayama et al. (Miarobial, Imrn.
wnol,.

-33- Vol., 22.89.1978). The defective material is the N-(ci) of the present invention.
For s-3,4-dimethoxycinnamoyl)anthranilic acid [cis compound] and tranilast, +71 difference was also 2
% gum arabic solution Rv to induce PCA reaction 1
The reduction rate was determined by the following formula.

CDc: Amount of dye leakage in the control group DT: tL Amount of dye leakage in the test drug administration group [Results] The results of the rat homologus pCA reaction are shown in Table 5 below. As is clear from Table 5, the N-
(cis-3.4-dimethoxycinnamoyl) anthranilic acid exhibited a significant inhibitory effect of approximately 50% when administered orally at doses of 100 and 3001119/kg, and its effect was much stronger than that of tranilast. It is.

/ Table 5: Rat omologous PC.

(3) Minimum lethal dose of N-<aim-3,4-dmethoxycinnamoyl of the present invention using ICR male mice with a body weight of 24-29.9.
Anthranilic acid [cis compound] and N-(trαn5
-3,4-Dmethoxycinnamoyl)anthranilic acid [tranilast] was orally administered, and animals were sacrificed for 3 days after drug administration to determine the minimum lethal dose. The results are shown in Section 6 below. & shown.

As is clear from the sixth paragraph, when administered orally, the cis-compound of the present invention has almost the same lethality as tranilast.

37- Next, the present invention will be further explained by referring to Reference Examples, Examples, and Ratio *9 column.

Reference Example I To a solution of C48-3, 4-claw) cinnabar bark #291 in tetrahydrofluff (30 m/), add 9 volumes of isobutyl chlorocarbonate (1,5 #1), cool with water, press forward, and add triethylamine (1,071 of tetrahydrofuran (5s/l
Add the solution dropwise and stir at room temperature. Ethyl acetate (60 td) was added to the reaction mixture, washed with water, dried over magnesium sulfate, and the medium was distilled off under reduced pressure to give anhydrous cis-
Isobutyl 3,4-dimethoxycinnamate carbonate (Z9g)
is obtained as a yellow oil, Infrared absorption spectrum (KBr, ICIn-"1 Nuclear magnetic resonance spectrum <90 MHz, CDCl3, δ) 0.9 't (d, CHtcH,) *, 677) 20
3 (m, CH, 1H) 3.92 (t, OCH, buy 2.6H) 4.06 (d
, OCR,,2H) 5.80 (d, C=CH, IH) 6.81-7.87 (m, C, H=C and hyphenyl 2, 4H) Reference example 2 Cim-3,4 - Add sodium dimethoxycinnamate and stir at room temperature for 150 minutes. Ethyl acetate (1s Od) was added to the reaction mixture, washed with a 5% aqueous sodium carbonate solution and water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oily Gia-3,4-dimethoxycin. Isobutyl acid carbonate (21θ■) is obtained. The infrared and nuclear magnetic resonance spectra were consistent with the product of Examination Example 1.

Reference row 3 Sodium eta-3,4-dimethoxycinnamate (20
0q) of benzene (5id) fi7 under stirring under water cooling.
Add isobutyl chlorocarbonate (150 wg) and stir overnight at room temperature. The following post-treatment was carried out in the same manner as in Reference Column 2 to obtain yellow oily isobutyl cis-3,4-dimethoxycinnamate carbonate (2001NiI).The infrared and nuclear magnetic resonance spectra were consistent with the product of Reference Example 1. Reference example 4 C4a-a, sodium 4-dimethoxycinnamate (20
Add isobutyl chlorocarbonate (150 ml) dropwise to acetone (5 dl & 4 ml) under water-cooling and stirring, and stir at room temperature for 1 hour. Same as Reference Example 2. Cim-3,4-somethoxycinnamate carbonic isobutyl (260 μm) was obtained. The infrared and nuclear magnetic resonance spectra were consistent with the product of Reference 1t!I1.

! -1! Example l Anhydrous cis -3* 4-dimethoxycinnamate isobutyl carbonate (900 η) in tetrahydrofuran (10 fne
1 solution under ice-cooling and stirring, add methyl anthranilate (490
M+) in tetrahydrofuran (5-1 solution) was added dropwise, -
Heat to reflux overnight. Ethyl acetate (300-
) in 5% sodium bicarbonate aqueous solution, 5% 4[
, and water, drying with magnesium sulfate, and distilling off the solvent under reduced pressure. The residue (89 Gy) was recrystallized from soisopropylether to give N-(aim-3,4
-dimethoxycinnamoyl) methyl anthranilate (6
90■) is obtained as pale yellow crystals. mp'r't42- -79°C.

Infrared absorption spectrum (KBr, tx-”)
H: 3310.3270 c (0:1690:1675 nuclear magnetic resonance spectrum (90 MHz, CDCl, δ
) 178, 3.82 ('cn, t' is 8.0CH8%
l, δ) 3.861a, C00CH,,3H) 6,02 (d% C=CH,1H) 6.73-8.861? 7L, CB=C and phenyl hydrogen, 8〃) 11.10 (Jl, C0NH11HI 1-liquid 1 mouth, Madography (silica gel; isopropyl ether/ethyl acetate/acetic acid = 30:5:1) R/
=0.66 Example 2 Anhydrous G-8-3.4-nomethoxycinnamate isobutyl carbonate (190 μl) was added to a solution of benzene (5 gntl) in ice-cold i
t4't! Below, a solution of methyl anthranilate (93,1) in tetrahydrofuran (2-) was prepared and heated overnight. The reaction metal was added to a 5% aqueous solution of sodium hydrogen carbonate, 5
% hydrochloric acid and water, and then in the same manner as in Example 1 to obtain methyl N-(cis-3,4-dimethoxycinnamoyl 1-anthranilate (xilv)) as pale yellow crystals.
77-79°C, infrared and nuclear magnetic resonance spectra were consistent with a product of 1+lll solid foam.

Example 3 Anhydrous cis-3,4-dimethoxycinnamate isobutyl carbonate (1,5,91 in tetrahydrofuran (10 m/)
To the solution was added dropwise 1'd of anthranilic acid (o, 67#) in tetrahydrofuran (5 + dl) under stirring under water cooling, and the mixture was heated to reflux overnight. To the reaction mixture was added ethyl acetate (30 dl, and diluted with 5% hydrochloric acid and water. After washing and drying with magnesium sulfate, the solvent is distilled off under reduced pressure.
) was recrystallized from diisopropyl ether to give N-(c
is-3,4-somethoxycinnamoyl)anthranilic acid (1,35, IF l is obtained as pale yellow crystals;
14a~144℃ Red MJL collection subel (KBr, l:1 to -1) 1/
7y H23810,3270 Sico=1690.16'75 Nuclear magnetic resonance spectrum (90#Hg%DMSO-d6,
δ) 3.65, 3.77 (8 respectively, OCR, 2.6.
1 6.07, 6.84 (respectively d, CH=CH.

2H) 6.88~&681m, phenyl hydrogen, 7H) 4I-chromatography (-(silica gel; benzene 45-/acetic acid = 20:1) Rf = 0.22 Example 4 Anhydrous cis-3,4-dimethoxycinnamate Isobutyl acid carbonate (6s o1n91 of tetrahydrofuran (5-)
Sodium anthranilate (351
Add 5 ml solution of 79) to 3 cups of water and heat to reflux.
After that, it was extracted with ethyl acetate, washed with 5% hydrochloric acid and water, dried over magnesium sulfate, and then the 1# medium was removed. After crystallization, N-(cis-3,4-somethoxycinnamoyl)anthranilic acid (425#f) was obtained as pale yellow crystals. Agreed.

-=1　6- Example 5 oss -3F 4-somethoxysilica silicate (s o).

Tetrahydrofuran (s mtr + gdl) was added with isobutyl chlorocarbonate (33 (My)), and under water-cooled stirring, a solution of triethylamine (250 ml of tetrahydrofuran (1,27 mmol) was added dropwise to the mixture at room temperature.
Stir the heron. The reaction mixture was cooled again on ice, and while stirring, a solution of anthranyl # (330 hl) in tetrahydrofuran (8-) was added to the solution of ethyl acetate (30 ml), and then the core temperature was added to the reactant mixture. 210 g) and 5% salt
! ? After washing with water and drying with magnesium sulfate, the solvent was distilled off under reduced pressure, and the azuke was recrystallized from soysoderobyl ether to obtain Tanyaei 4N-(cis-3,4-dimethoxycinnamate). Moyl) anthranilic acid (545m91
The obtained Hyxp, 143-144°C infrared and nuclear magnetic resonance spectra are consistent with the main component of Example 3.

Example 6 ci8-3.4-sometocincinnamic acid (500IntI
) 114 chloroformamide (3-) solution to the methylformamide (5-) solution]-7, = γ1j80°
Heat at C6. , After distilling off the binding medium under reduced pressure, the residue was
Eh, 5 'Vo cloth, wash and sew with water, take care of the mug, tsum, 吃S, distill off the solvent in the 戊j 王CHO, remove the solvent, reconstitute from r-sopropyl ether, t& Please, N-(
Obtain czs-3,4-dimethoxycinnamoyl)anthranyl #(5f14mg> as pale yellow crystals; mp
The 143-144°C infrared and nuclear magnetic resonance spectra were consistent with the product of Example 3 fc.

Example 7 cis-3,4-V methoxycinnamic acid (500 Wf
) in tetrahydrofuran (8d), add ethyl chloride carbonate (26111), press water cooling +1, add triethylamine (243~+) to tetrahydrofuran (L2
Add 1 hour of reaction mixture and stir for 1 hour at room temperature.
Drop 5 m of (nu's tetrahydrofuran tsti) m solution and let Masakata move. Hereinafter, in the same manner as in Example 5, N-(cis-3゜4-dimethoxycinnamoyl)anthranilic acid (320■) was obtained as pale yellow crystals.
m9.

The 143-144'C infrared and nuclear magnetic resonance spectra were consistent with the main component of II3.

Implementation-8 ois-3,4-dumethoxycinnamic acid (20Ii)-
49- of tetrahydrofuran (32 mg)
) Add 3 portions of the solution and stir at room temperature for 1 hour.

The reaction mixture was cooled again with water (7, tetrahydrofuran C4- of methyl anthranilate (1,69) with stirring).
The solution is heated to reflux.

Hereinafter, the post-treatment was carried out in the same manner as in Example 1, and pale yellow crystals of methyl N-(cis-3,4-dimethoxycinnamoyl)anthranilate (Z8.Ii'1141+temporary p. 77
~79°C Infrared and nuclear magnetic resonance spectra were consistent with the main product of Example 1.

Example 9 cis-3,a-somethoxycinnamic acid (500111i
) of tetrahydrofuran (8 m/) @fiK chloroethyl carbonate (26 x 1!
50-Ethylamine (243■) in tetrahydrofuran (1
, 2rnt 1 solution was allowed to evaporate, the mixture was stirred for 1 hour at room temperature, cooled again with water, and anthranyl 14I methyl (363~) was dissolved in tetrahydrofuran (
1.2 m/) solution was added to the thread, and the solution was heated to reflux.

Hereinafter, in the same manner as ψ defect example 1, pale yellow crystal N-(ci
s-3,4-dimethoxycinnamoyl) methyl anthranilate (340rll 11-m177~79°C Infrared and cough magnetic A/b spectra are those of the product of Example 1 j
matched.

Infusion Example 5 To methyl N-(cis-3,4-dimethoxycinnamoyl)anthranilate (2,5,!/l, add 10% sodium hydroxide aqueous solution (25 mgl) and ethanol (15-1), and heat at 90°C. After cooling, acidify with 10% hydrochloric acid, and extract with ethyl.
After washing with water and drying with magnesium sulfate, press
The /4 medium is distilled off. The residue was recrystallized from neuisoprobyl ether to give pale yellow crystals of N-(cis-3,4
-dimethoxycinnamoyl)anthranilic acid (Z3.+
mp143~1446C infrared and nuclear @ 5.4 The spectrum is real TFR[91
13 products were found.

Comparative Example l Cis-3,4-dimethoxycinnamic acid (210q) was prepared according to the method of Example 1 in the Bulletin of Japanese Patent Publication No. 57-36905.
Thionyl chloride (07+
After adding ++e) and heating under reflux for 2 hours, the reaction solution was concentrated under pressure to obtain an oily acid chloride.

Its nuclear magnetic resonance spectrum (90 Mllz, CDCl,
, δ) is &93(s, OCHs x 2, 6H), 6
, 52 (d, C=C1, lB), 686-7.36 (
m, phenyl hydrogen, 3H), 7.80id, CH=c,
lH), which is separately adjustable trans -3
, 4-somethoxycinnamic acid chloride, and no presence of C1a was observed. For further confirmation, the above crude acid chloride and methyl anthranilate were condensed as follows - Methyl anthranilate (180 tries) and baboon IJ dun (100 μl) were placed in a solution of chloroform (2 mA) in an ice-cold solution. Press down, add dropwise the previously prepared solution of crude acid chloride in chloroform (5-), and heat constant-reaction mixture 2 at 50°C for 3 hours.
The proboscis was concentrated under reduced pressure and the residue was poured into water and then acidified with hydrochloric acid. The precipitated crystals were taken out and recrystallized from aqueous ethanol to obtain methyl anthranilate (230 Wle).

Melting point 143-145℃ -53- Infrared absorption spectrum/l/(KBr, ,rn-
'1νc0 1705.168゜Nuclear magnetic resonance spectrum (90AfHz, DMSO
−d6, δ) 3.81, 3.87 (respectively 8, ocH,,2, r,
El) &91 (8, C0QCH,,3H1 6,7~&61 m, Cl1=CII and phenyl hydrogen, 9H) Also, Furnace I\'s Hiromi # Chromatography (T LC;
Silica gel; in isopropyl ether/ethyl acetate/acetic acid = 30:5:11, the corresponding N-<C1m-3
, 4-dimethoxycinnamoyl) methyl anthranilate spot (R1 = 0.591) was not observed.

Comparative Example 2 Ice-cooled thionyl chloride (cis −5 in &5tdl)
4- Suspend 500 mgl of 3.4-dimethoxycinnamic acid,
Add triethylamine (243■) to room temperature for 3 hours.
Blue stirred. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (10+++j!l). Separately, methyl anthranilate (363cm) and triethylamine (243cm)
'mg1 paste chloromethane (10ml11 solution prepared,
The dichloromethane solution prepared above was added dropwise to this solution before cooling with water, and the mixture was stirred at room temperature for 3 hours.

TLC of the reaction mixture (silica gel; isopropyl ester/ethyl vinegar/acetic acid = 30:5:11 was N-
The spot corresponding to methyl ans-3,4-dimethoxycinnamoyl)anthranilate (R, (=0.591
However, the spot Qi of cis-H (Rt = 0.661) was not observed.This reaction mixture was diluted with 5% 4
Acid, 5% hydrogen carbonate) Wash and wire with IJum and water;
The solvent was distilled off under reduced pressure and the residue was recrystallized from aqueous ethanol to give N-(tr).
Ans-3,4-dimethane Comparative Example 1 was consistent with the main formation.

Comparative Example 3 Cis-3,4-dimethoxycinnamic acid (620
/Qgl and methyl anthranilate (496~) in sooxane (8.7 dl solution), oxychlorinated phosphoric acid (50
8...t) and sodium carbhydrogen (600111i) were injected, and 2[Terama heating was carried out].

TLC of reaction mixture', i:il (silica gel; isopropyl ether/ethyl acetate/acetic acid = 30:5:11 is R
f==o, s'l received a spot of N-(trans-3,4-dimethoxycinnamoyl)anthracaranilic acid, but the corresponding cis-integrated spot (Rf=0.66)
was not recognized. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 10% sodium hydroxide solution (15 mA).
was added and heated in a water bath for 1 hour. Reika・, 1 catty of tran is divided into several units, washed with water, recrystallized from water, and N-(tran)
Sodium s-3,4-somethoxycinnamoy+1.) and intratranyl 1.2% (670 u..v) was obtained.

ma 196-200°C Infrared absorption spectrum (KBγ, ('In'1νco
1660 nuclear magnetic spectrum (90MHz, DAISO-
do, δ) 3.79, 3.82 (respectively 8, OC7/, 2.
6Z/1 6.47-8.7 (m, CH=CH and 7m nil hydrogen, 9M) Ratio + gy Example 4 Example 12-5 of Publication No. 56-40710
According to method 7-1, cis-3,4-somethoxycincinum ff
(300 fn!, l of pyridine (3-) solution was added with benzenesulfonyl chloride (250 ~) and stirred at room temperature for 3 hours. Then, anthranilic acid (2001Iv)
A solution of pyrimidine (l-) was added dropwise thereto, and the mixture was stirred overnight at M. TLC of the reaction mixture (silica gel, benzene/acetic acid = 2o:11, Rf = o, tatrN-1tran
The spot of s-3,4-dimethoxycinnamoyl)anthranilic acid is shown, but the corresponding C1a integral (/?/
=0.221 spot was not observed. The reaction mixture was condensed once under reduced pressure, and the residue was poured into ice water and acidified with hydrochloric acid, and the precipitated crystals were separated. This was dissolved in 70% aqueous ethanol (5d) and concentrated hydrochloric acid 10.11! m/)
was added and heated under reflux for 30 minutes. The reaction solution was incubated, the residue was poured into ice water, and the precipitated crystals were recrystallized from chloroform to give N-(trans-3,4-dime5
8-Toxycinnamoyl) anthraniil (3201v
I got l. The melting point, infrared and nuclear magnetic resonance spectra were consistent with the data for tranilast.

Comparative Example 5 Cis-a, 4-somethoxycinnamic acid (
A solution of pyridine (1+nt) of benzenesulfonic acid chloride (360ZV 1) was added to a solution of pyridine (2 + + + 420 ~) under cold stirring and stirred at room temperature for 2 hours. 320η) of Virimison il+++7!L solution was lowered to 100°C.
It was heated at 1,511V 1ifi. TL of reaction mixture
Cl silica gel, isozorobyl ether/ethyl acetate/
Acetic acid = a O15/1) is N-(t
A spot of methyl rans-3,4-dimethoxycinnamoyl) anthranilate was shown, but the corresponding cia-integrated spora) (Rf = 0.661 was not observed.
The reaction mixture was condensed, and the residue was poured into ice water, acidified with hydrochloric acid, and extracted with chloroform.

After washing the extract with water, sodium bicarbonate solution fA, and water in this order, the mixture was condensed under reduced pressure, and the residue was poured into ice water and then made acidic using a vacuum cleaner. , took all the crystals from one loaf, crystallized them from aqueous ethanol, and obtained N-(trα'n8-3.4-
Dimethoxycinnamoyl) methyl anthranilate + 4
10471171 was obtained, and the melting point, infrared and nuclear magnetic resonance spectra were consistent with the main product in column 1 of 112. To 15111 ml of trimethylformamide (1 ml) @Ql was cooled with water and stirred for 5 hours at room temperature, followed by addition of sophenyl phosphoric acid asodo (303), trimethylformamide (1414a) and triethylamine (121). TLC of reaction mixture (silicage gel, isopropyl ether/
Ethyl acetate/acetic acid = a o, /s/ + l riRf
= spora of N-(trans-3,4-dimethoxycinnamoyl)methyl anthranilate in o, s'f) (R
The corresponding cis-(4) spot (Rf = 0.661 was not observed. After washing with sodium carbonate water, sodium chloride solution, 5% hydrochloric acid, and salt solution, and drying with magnesium sulfate,
The solvent was distilled off under reduced pressure, and methyl N-(trans-3,4-dimethoxycinnamoyl)anthranilate (300
■) was obtained. The presence of cja book was not observed in this product in nuclear magnetic resonance spectroscopy and TLC.

61-

Claims (1)

[Scope of Claims] 1. Anhydrous cja-3.4-nomethoxycinnamate carbonate monozoate carbonate monoester carbonate linear atom or carboxyl represented by the formula, where R represents a monovalent hydrocarbon group In the formula, Z has the above meaning, N-(aim-3,4-somethoxycinnamoyl)anthranyl represented by Method for manufacturing layer compounds. 2. The compound of formula (1) is converted to cts-3,4-somethoxycinnamic acid represented by the formula in the presence of a base or in the form of a salt, where R represents a monovalent hydrocarbon group. 2. The method according to claim 1, which is produced by reacting with a chlorocarbonate represented by , at a temperature below about room temperature. Anhydrous cis-3,4-dimethoxycinnamate carbonic acid monoalkyl ester represented by 1 formula % formula % where R' represents a lower alkyl group.