JPS5846051A - Aminocarboxylic acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI[R<1> is acyl or alkyloxycarbonyl; X<1> is 3-6C alkylene, 1,4-cyclohexylene, etc.; R<2> and R<3> together from oxo group or R<2> is OH and R<3> is H; X<2> is 1-6C alkylene; R<4> is COOR<5> (R<5> is H or 1-6C alkyl) or CH2OR<6> (R<6> is H or 1-6C acyl)]or a salt thereof. EXAMPLE:3-[p-(4-N-Acetylaminomethylcyclohexylcarbonyl)phenyl]propionic acid. USE:An antiulcer agent. PROCESS:An aminocarboxylic acid halide of formula II (Hal is halogen) is acylated with a compound of formula III[R<41> is COOR<51> (R<51> is 1-6C alkyl) or CH2OR<61> (R<61> is 1-6C acyl)]in the presence of a Lewis acid, and if necessary hydrolyzed or subjected to the salt-forming reaction to give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel aminocarboxylic acid derivative and a method for producing the same. More particularly, the present invention relates to a novel aminocarboxylic acid derivative that is expected to be used as a pharmaceutical agent such as an anti-ulcer agent, and a method for producing the same.

According to the present invention, a novel aminocarboxylic acid derivative represented by the following formula [[] or a salt thereof is provided.

On the other hand, 1 article Journal of American Chemical
Tsunaiety (Journal of America)
an Chemical 8ociety), I
I 1%.

11159.4 @ 39-4643. , 3-(p-aminoacetylphenyl)propionic hydrochloride represented by the following formula % is described as an intermediate of clotumbucil (c, hrorambucil) having anticancer activity 5.

Japanese Unexamined Patent Publication No. 134/1983 describes amino acid esters having an anti-ulcer effect represented by the following formula: H*MCH@be→...0OOQ.

However, the above-mentioned aminocarboxylic conductor provided by the present invention has a structure different from those of these known compounds, and is a new compound that has not been published in any literature, and its pharmacological action is different from that of these known compounds. It is a compound that is expected to be used as a pharmaceutical product such as anti-ulcer agents, and is also expected to be used as a precursor of pharmaceutical products such as anti-ulcer agents.

The aminocarbon #i14 body of the above formula [I] is R1゜H
Based on the definition of a, it can be divided into the following compounds.

That is, an aminocarbon soap derivative or a salt thereof represented by the following formula [1]-a [wherein R', X', X'' and R4 are the same as defined above] and the following formula [1]-1 OH R1wHaH Snow-xI-OH-()-X"-R'
-----・-[1] -b [wherein, R', r, X
4 and W are the same as defined above. ] or a salt thereof.

Among this group of compounds, the group of compounds represented by the above formula [1)-a is particularly preferred.

In the above formula, R' is an acyl group or an alkyloxycarbonyl group. As an acyl group, for example, carbon number is 1~! 2
An acyl group of a carboxylic acid is preferred. Especially carbon number 1
-7 carboxylic acid acyl groups are preferred. Examples of such acyl groups include formyl, acetyl, propionyl,
butyryl, valeryl, caproyl, heptanoyl.

Preferred examples include octanoyl, nonanoyl, decanoyl, undecanoyl, and lauroyl.

Preferred examples of the alkyloxycarbonyl group include t-butoxycarbonyl, ethyloxycardanyl, diisopropylmethyloxycarbonyl, and the like.

Among these, R1 has a special acetyl group.

zl represents an alkylene group having 3 to 6 carbon atoms, L4-cyclo is a silene group, or L4-phenylene group. Carbon number 3~
Examples of the alkylene group of 6 include trimethylene group, detramethylene group, pentamethylene group, hequinamethylene group, and the like.

xl is an alkylene group having 1 to 6 carbon atoms, and these alkyref groups may be substituted with an alkyl group having 1 to 6 carbon atoms.

Examples of the alkylene group having 1 to 6 carbon atoms include methylene, dimethylene, trimethylene, tetramethylene, and pentamethylene. Examples of the alkyl group having 1 to 6 carbon atoms as a substituent include methyl, ethyl, nf-propyl,
igo-furovir, n-butyl, 180-butyl, t
@rt-Butyl, n-pentyl, n-hexyl, etc. can be given.

Among these, xl is preferably a methylene group or a dimethylene group.

R4 is a group represented by 100 OR' or -0 OR'.

When R4 is 100OR', R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. That is, when R1 is a hydrogen atom, R4 is a carboxyl group, and R1 has 1 carbon number.
-6 alkyl group, R4 is an ester group. Examples of the alkyl group having 1 to 6 carbon atoms are the same as those exemplified above for I''K.

When R4 is -CiOR', R6 is a hydrogen atom or an acyl group having 1 to 6 carbon atoms. That is, when R. is a hydrogen atom, R4 is a hydroxymethyl group, and when R@ is an acyl group having 1 to 6 carbon atoms, R4 is an ester group. Examples of the acyl group having 1 to 6 carbon atoms include formyl, acetyl, gropionyl, butyryl, valeryl, and cabroyl group rings.

Among these, R4 is particularly preferably -00OR'', and in the above formula [1], when it is !'#L4-cyclohexylene/ group, it may be in either a chair-shaped or boat-shaped form; The two bonds may be in a cis relationship or in a trans relationship.Preferably, they are in an S trans relationship in the chair-shaped shape 11JK.

Aminocarboxylic acid derivatives of the present invention (, l When R4 is a carboxyl group (when R1 is a hydrogen atom), it can be a salt at this carboxyl group. As a salt at a carboxyl group, an alkali Preferred examples include salts with metals, 1/2 equivalent of alkaline earth metals, 1/3 equivalent of aluminum, ammonium, etc. Among them, 41 is lithium.

Salts of sodium, potassium, 1/2 calcium, 1/2 magnesium, and 1/3 aluminum are preferred.

I' represented by the above formula [1] provided by the present invention
Examples of compound b include the following compounds.

(loo), s-[p-(4-w-acetyl-r-methylcyclohexylcarbonyl)phenyl]globionic acid.

(102), s-(p-(4-M-propionylaminomethylcyclohexylcarbonyl)phenyl)
Propionic acid.

(104), s [p-(4-II-cabroylaminomethylcyclohexylcarbonyl)phenyl]
Propionic acid.

(106), 2[p-=<4-)I-acety7minomethylcyclohexylcarbonyl)phenyl]propionic acid.

(1 bottle), 2-(p(4N-acetylaminomethylcyclobenzylcarbonyl)phenyl) vinegar soap.

(110), 4-[p-(4-N-acetylaminomethylcyclobenzylcarbonyl)phenyl]butyric acid.

(112), 1-[p-(4-N-7-ni-methyl7-methylcyclo-methylcarbonyl)phenyl]
Methyl propionate.

(114), 11-(p-(4-M-propionyl-ζmethylcyclohexylcarbonyl)phenyl]fropionethyl.

(11 g), s-(p-(4-N-cabroylaminomethylcyclohexylcarbonyl)phenyl]fropion butyl.

(us), z-(p-(a-M-acetylaminomethylcyclohexylcarbonyl)7enyl)methyl acetate.

(!+), 4 [p-(a-w-acetylaminomethylcyclohexylcarbonyl)7enyl]methyl butyrate.

(122), s-(p-(a-H-acetylaminomethylcyclohetylcarbonyl)fe-nil) propatool.

(124), '2-[p-(4-M-acetylaminomethylcyclohexylcarbonyl)phenyl]ethanol.

(1 decoration), 4-[:P-(4-11-acetylaminomethylcyclohexylcarbonyl)phenyl]butanol.

(Dark 3-(p-(4M-acetylaminomethylcyclohenylcardanyl)phenyl)propyl acetate.

(13G), 2-[p-(4-M-acetylaminomethylcyclohexylcarbonyl)phenyl]ethyl acetate.

(132), 4 (p-(4-M-acetylaminomethylcyclohexylcarbonyl)phenyl cobutyl acetate.

(134), *-Cp-(4-M-acetyla2)methylbenzoyl)phenyl]globion.

(136), 3-(p-(4-M-acetylaminomethylbenzoyl)phenyl)gropionenthyl.

(138), butyl 3-(p-(4-N-acetylaminomethylbenzoyl)phenyl]cropionate.

(14G), 2-Cp-(a-w-acetylaminomethylbenzoyl)phenyl:] vinegar ii.

(142), z-(p-(4-M-acetylaminomethylbenzoyl)phenyl)methyl acetate.

(144), 4-(P-(4-N-acetylaminomethylbenzoyl)phenyl)M.

(1463,4-(p-(4N-caproylaminomethylbenzoyl)phenyl)fill methyl,
- (la), s-(p-(4-m-acetylaminomethylbenzoyl)phenyl)propertool.

(150), 3-[1)-(4-N-acetylaminomethylbenzoyl)phenyl]furovylacetate.

(152), 2-[p-(4-N-caproylaminomethylbenzoyl)phenyl]ol.

(164), s-[p-(4-M-acetylaminomethylbenzoyl)phenyl]ethyl acetate.

(lss), a-[p-(J-M-zucetylaminovaleryl)phenyl]guapionic acid.

Dss), s-[p-(a-N-7-ni?/cacroyl)phenyl]propionic acid.

(159), s-(p-(·-N-acetylaminooctanoyl)phenyl)propionic acid.

(16G), 3-(p-(fist-N-acetylaminohebutanoyl)7enyl)propionic acid.

(ii1. Methyl s-[p-(g-M-acetylaminocafroyl)phenyl]propionate.

(162), a-(p-(a-N-acetylaminovaleryl)phenyl]gropionyl methyl.

(164), R(p(a-M-acetylaminocaproyl)phenyl]butyl globionate.

(lss), s(p(#N-acetylaminooctanoyl)phenyl)methylglobionate.

(***), x-[p-(a-N-acetylaminocafroyl)phenyl]acetic acid.

(168), 4-[p-(a-N-acetylaminocaproyl)phenyl]1111° (17G), 3-(p(aM-acetylaminocafroyl)phenyl)gropanol.

(172), 3-(P-(#-M-acetylaminocaproyl)phenyl]propyl acetate.

(174), 3-(p-(a M-acetylaminocafroyl)phenyl]ethanol.

(IM), 4-(p(a M-acetyl aceticabroyl)phenyl]ethyl acetate.

Similar to these compounds, the following compounds are exemplified.

Compounds (l@) ~ (110), (134), (14
G), (144).

Sodium salt, potassium salt, calcium salt, aluminum salt of (la6) to (1@), (tag) to (168).

A good compound (ZGo) ~ (13 riha shikuo hexa7m
Regarding K, mK can be in the form of trans form, cis form, or a mixture thereof.

(ii) a compound (w) represented by formula [I]-b,
5-(p-(4-N-acetylaminomethylcyclohexylhydroxymethyl)phenyl]gropionic acid.

('x2. 2-(p-(4-Acetylaminomethylcyclohexylhydroxymethyl)phenyl)acetic acid.

(+o4), 4-(p-(4-x-acetylaminomethylschiffchohexylhydroxymethyl)phenyl]butyric acid.

(206), s-[p-(4-w-acetylaminomethylcyclohexylhydroxymethyl)phenyl]methyl phlopionate.

(20B), 2 (p-(4N-acetylaminomethylcyclohexylhydroxymethyl)phenyl]
Methyl acetate.

(210), 3-[p-(4-N-acetylaminomethylcyclohexylhydroxymethyl)phenyl]propertool.

(212>, 2-Cp-(4-x-acetylaminomethylcyclohexylhydroxymethyl)phenyl]ethanol.

(2i4), 3-(p-(4-N-acetylaminomethylcyclohexylhydroxymethyl)phenyl]propyl acetate.

(216), *-[p-(4-M-acetylaminomethylphenylhydroxymethyl)phenyl]propionic soap.

(218), methyl 3-[P-(4-N-acetylaminomethylphenylhydroxymethyl)phenyl]globionate.

(221))-2[p-(4-M-y*thylaminomethylphenylhydroxymethyl)phenyl]acetic acid.

(222), 3 (p-(411-acetylaminomethylphenylhydroxymethyl)phenylcoglobanol.

(224), 3-[p-(6-N-acetylamino-1-hydroxyhexyl-1-4yl)phenyl]propionic acid.

(膓), 3-[p-(t-N-acetylamino-1-hydroxyoctyl-1-4yl)phenyl]propionic acid.

(228), 2-[p-(ax-acetylamino-!-hydroxyhexyl-1-4yl)phenyl]acetic acid.

Similar to these compounds, the following compounds are also exemplified.

Compounds (200) to (204), (21g),
Sodium salts, potassium salts, calcium salts, and aluminum salts of (220), (224) to (228).

Compounds (200) to (214) are trans isomers with respect to the cyclohexane ring.

It can be in the form of cis form or a mixture thereof.

The compound represented by the above formula [i] provided by the present invention can be produced as follows.

'Manufacturing method-a According to the present invention, the following formula]-a [wherein R', X'', X'' and t are the same as defined above. ]
The aminocarbon derivative or its salt represented by the following formula [111].

Aminocarboxylic acid halide represented by the formula % [ and the following formula [
[厘] A compound represented by eSx''-R゛...[厘] is subjected to an acylation reaction in the presence of a Lewis acid, and then subjected to hydrolysis and/or salt-forming reaction as necessary. Manufactured by KotoK.

In the above formula [■], the definitions of R1 and 11 are the same as in the above formula [2], and HaL represents a halogen atom, preferably a chlorine atom or a bromine atom. The aminocarboxylic acid halide represented by the above formula can be produced by a known method of reacting the corresponding aminocarboxylic acid with a halogenating agent such as thionyl chloride, phosphorus trichloride, or phosphorus pentachloride.

In the above formula [11, which is the other raw material, x snow is the same as in the above formula [11K], and R4- represents -0OOR'' or -0HtOR''. Here, R” has 1 to 6 carbon atoms.
R@lFi is an acyl group having 1 to 6 carbon atoms. Such alkyl groups and acyl groups are represented by the above formula [1]
The same examples as those exemplified in .

Examples of the aminocarboxylic acid halide represented by the above formula [0] include the following.

4-4-acetylaminomethylcyclohexanecarboxylic acid chloride.

4-N-acetylaminomethylcyclohexanecarboxylic acid bromide.

4-M-A7tylaminomethylbenzoic chloride.

sN-acetylaminocaproic acid chloride.

Examples of the compound represented by the above formula [厘] include the following.

Methyl 3-phenylgropionate,' Ethyl 3-pheerglobionate.

3-phenylpropylacef-).

Methyl 4-phenylbutyrate.

Ethyl 4-phenylbutyrate.

The above acylation reaction of the present invention is carried out by reacting the aminocarboxylic acid halide of the above formula [8] with the compound of the above formula [I] in the presence of a Lewis acid. Examples of Lewis acids include aluminum halide compounds such as aluminum chloride and aluminum bromide; zinc halide compounds such as zinc chloride; iron halide compounds such as ferric chloride; Preferred examples include tin yyride compounds; and halogenated titanium compounds such as titanium chloride. Among these, aluminum halide compounds and zinc halide compounds are particularly preferably used.

The reaction is stoichiometrically a combination reaction of 1 mole of the aminocarboxylic acid halide of the general formula [layer] and 1 mole of the compound of the general formula [1], but the stoichiometric amount of either one is There is nothing wrong with using a large amount of it. Usually, the quantitative ratio of one to the other is α1~
It can be used in a range of 10 times.

Since the reaction proceeds without heat generation, the Lewis acid is preferably used in an amount of about 1 to about 20 mol, more preferably about 1 mol, per mol of one of the raw materials used, which has a smaller quantitative proportion. ~20 mol, particularly preferably from about 2 to about S mol.

Although the presence of a reaction medium is not essential for the reaction to proceed if the compound of general formula [厘] exhibits a liquid state under the reaction conditions, the reaction is preferably carried out in the presence of a reaction medium. As the reaction medium, aprotic inert organic solvents are preferred, such as chlorofor^, carbon tetrachloride, dichloromethane, dichromitane, tetra, chloroethane, cyfuromoethane, fromobenzene.

Halogenated hydrocarbons such as chlorobenzene: hexane.

Hydrocarbons such as heptane, cyclohexane, and ligroin; nitrobenzene, carbon disulfide, and the like are used.

The reaction is preferably carried out at a temperature usually between about 10°C and the reflux temperature of the reaction system. Particular preference is given to carrying out at temperatures between room temperature and 80°C.

When carrying out the reaction, the compound of the above formula [seal] is added to the mixture of the aminocarboxylic acid halide and the Lewis acid in the reaction medium, or the compound of the above formula [m] is mixed with the aminocarboxylic acid halide and the compound of the above formula [m]. Preferably, either the Lewis acid is added little by little to the mixture in the reaction medium, or the aminocarboxylic acid halide is added to the mixture of the compound of formula [sulfuric acid] and the Lewis acid in the reaction medium. Adopted. Among these, the first operation is particularly preferably employed.

The reaction usually completes in about 5 minutes to about 24 hours.

After the above acylation reaction, the target product is purified in the following manner.

That is, water or an aqueous solution of a basic compound such as sodium hydride:potassium hydroxide, sodium carbonate, potassium carbonate, etc. is added to the reaction mixture or residue to first decompose the Lewis acid.

Thereafter, when the reaction solvent becomes an extraction solvent, K may separate the product as a solution in the reaction solvent. When the reaction solvent is not used as a rounding solvent for the extraction solvent, the reaction solvent is removed and ether, chloroform, l! S1 Extract with a water-immiscible organic solvent such as carbon chloride, carboxylic ethane, pe/zene, toluene, xylene, etc., or remove the reaction solvent and water and add a water-immiscible organic solvent and water to the resulting residue. Just add and extract.

The extracted and separated organic layer is then washed with water, dried, and dried to give the desired product.

The target product is obtained as a compound of the formula [1) -a in which R1 corresponds to a tkffl group such as an acyl group or an alkyloxycarbonyl group, and R4 is R41.

(1) The compound thus obtained may further contain -C
k x f k group (c oull or -〇 quick OR”)
is subjected to a hydrolysis reaction. Such hydrolysis is carried out by a method known per se using an acid or an alkali as a catalyst.

When suspended as a catalyst, the formula [1)-IL Kν
Then, an aminocarbon soap derivative in which R' is an acyl group or an alkyloxycarbonyl group, ibb, and R'' is -aoog or -CutOH is obtained.

Examples of acid catalysts include non-sulfuric acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, and phosphoric acid; organic carboxylic acids such as acetic acid, gropionic acid, and maleic acid; and organic sulfonic acids such as methanesulfonic acid and benzenesulfonic acid. It will be done.

After hydrolysis using an acid catalyst, the K that yields the target product is
The reaction mixture is usually evaporated to dryness, then water is added to the resulting 9 residue, extracted with an organic solvent, and the target product is separated from the resulting organic layer by a conventional method, or the residue is recrystallized. Alternatively, the residue is subjected to chromatography.

When an alkali is used as a catalyst, the formula [:I] −
In a, a compound is formed in which R' is an acyl group or an alkyloxycarbonyl group and R4 is a carboxyl group or -0EbOH in salt form 11.

Alkaline catalysts include sodium hydroxide, sodium carbonate, and sodium hydrogen carbonate.

Examples include potassium hydroxide and potassium carbonate.

To obtain the desired product when using an alkali catalyst,
Usually, an acid is added to the reaction mixture to neutralize the carboxyl group in the form of a salt, converting the carboxylate group to 1000H, and then separating the target product from the reaction mixture using an acid catalyst. All you have to do is perform the same operation as for the conditions.

(2) The compound thus obtained is l! If necessary, it is subjected to a salt-forming reaction.

That is, in order to obtain a compound in which R4 is -cooH in the salt form 11, a compound of the formula [I] in which R4 is 100 on is subjected to a neutralization reaction with a basic compound such as that used in the above-mentioned alkali catalyst. The reaction mixture is then evaporated to dryness, and the residue may be subjected to recrystallization or chromatography as appropriate.

Production method-b According to the present invention, the following formula [1] -b H amount R'1fHOH -xI-cH to yEx4-... [l
l-b [wherein R', X'', X'' and R4 are the same as defined above. ] The aminocarbon derivative or its salt represented by the following formula [11-R'WHO &-X'-06X''-R' .
... [1] IL [wherein R1, IS, 11 and R4
is the same as the above definition. ] The aminocarbon iron derivative represented by the following formula [fl M'(R' ), 4-4BIz s+**
**+** [Produced by reducing with a borohydride represented by yl, and then subjecting it to hydrolysis and/or salt-forming reaction as necessary.

In the borohydride represented by the above formula [W], M
I is an alkali metal or an equivalent of an alkaline earth metal, such as sodium, lithium A, potassium, 1/2 calcium, and the like.

R' is a lower alkyl group or a lower alkoxy group. Examples of lower alkyl groups include methyl, ethyl an
-Clovir, 1ao-Clovir n-butyl, 5ea-
Examples include alkyl groups having carbon atoms of 1 to 6, such as butyl.

Examples of the lower alkoxy group include alkoxy groups having 1 to 5 carbon atoms such as methoxy, ethoxy, 180-globogyoxy, and n-butoxy.

L is an integer from 1 to 4. At t-4, K is expressed as formula [1]
represents a compound in which R' is not present.

Specific examples of the borohydrides of the above formula [f] include 1, such as sodium borohydride, lithium borohydride, lithium triethylborohydride, and triethylborohydride 5ea-
Lithium butyl boron, sodium trimethoxy boron hydride, hydride chang yip. Potassium borohydride, potassium borohydride, calcium borohydride, etc. are preferably used.

Among these, lithium borohydride, lithium triethylborohydride, sodium trimethoxyborohydride, and potassium triisopropylborohydride are l1i
VcfFf is preferably used, in particular lithium borohydride and sodium borohydride.

The amount of the bulking compound CUE is preferably about 1 to about 20 moles, particularly preferably about 15 to about 1 mole, relative to the compound of general formula CD-a.

Used in moles.

As the inert solvent used in the reaction, ether or alcohol solvents are preferably used. Preferred examples of the ether solvent include diethyl ether, detrahydro7rane, dioxane, dimethoxyethane, triethylene glycol dimethyl ether, and diethylene glycol dimethyl ether. As an alcoholic solvent, it is particularly desirable to cool it at the initial stage of the reaction. The reaction is conducted at a temperature below the reflux temperature of the reaction system, preferably at a temperature of about SC to about SO<0>C.

Due to the above reduction, the above formula [11-! From the compound of L, x
A compound of the above formula (1)-b is obtained in which only the keto-carbonyl group in contact with 1 is a H droxymethidine group <-6g-)K11.

The compound thus obtained can be further subjected to hydrolysis and/or salt-forming reactions as described in Production Method-a, if necessary.

The aminocarbon derivative of the present invention thus produced is a useful compound expected to be used in pharmaceuticals such as anti-ulcer agents.

The present invention will be explained in more detail below by way of examples.

Example L Trans-4-M-acetylaminomethylcyclohexanecarboxylic acid chloride 3f was suspended in 50-carbon disulfide and mixed with aluminum chloride &s under water cooling while stirring vigorously.
After adding t, phenylpropionate methyl ester!
A solution of L3t and carbon disulfide 30m was added and heated under reflux for 25 minutes.
Stir for hours. After the reaction was completed, the solvent was distilled off, water was added to the residue, and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and after 9 days, the chloroform was distilled off under reduced pressure to form a pale yellow amorphous substance. can be obtained. This sample was subjected to column chromatography using silica gel as a carrier (#1 solvent: a mixed solvent of chloroform and ethyl acetate) to obtain the desired trix.
(tlz)aof (yield aa%) was obtained.

This material has the following physical properties and supports the structure.

NMR (CDC) # (ppm) Near, 11i (
2H, d, J = 15111g, benzene II Hs)
+7.25 (2H, d, J+45Hg, Bearzea glHB).

&8S(IH, m, CHs (! Ndan-
).

! +85 (IH, 11,0OOOHs).

tto4i, LO~Z2 (16II, m,
CHl- and cyclohexane IjIH@).

? 10 (11,s, OHs O-MH)
.

Example 2 The transformer (112)l f obtained in Example 1 was 2M@
The suspension was suspended in 930 ml and subjected to hydrolysis reaction at room temperature for 48 hours. After the reaction, hydrochloric acid was distilled off under reduced pressure, and the resulting residue was purified using Brevara Lype thin layer chromatography to obtain the desired trans(too) 845■ (yield: 88
嗟). This material has the following physical properties and supports the structure.

MMR (Meoa-aa), J (ppm) near, 1
1 (2H, (L, J=&5HI, benzene 11Hs)
.

t, zs (zH, a, J-asiz, penzey3jlH
g).

10 (311, s, OHs ONH).

LO~! 4 (16H, m, cyclohexane ring and 10Ht
−→.

Example λ 800 μl of 1-N-acetylaminocaproic acid chloride produced by reacting a-31-acetylantzukagulonic acid with thionyl chloride in benzene was suspended in 20× carbon disulfide and stirred vigorously. After adding aluminum chloride L3F while cooling with water, a solution of phenylglobionic acid methyl ester 550TII9 and carbon disulfide 5d was added and stirred under reflux for 4 hours. After the reaction is complete, the carbon disulfide layer is separated by decandation, and a small amount of ice water is carefully added to the residue to decompose excess aluminum chloride. An aqueous sodium hydroxide solution was added to the aqueous solution obtained in the boat to dissolve the resulting aluminum hydroxide, and then extracted three times with chloroform. After washing the chloroform layer with water and drying over anhydrous sodium sulfate, the chloroform was distilled off under reduced pressure to obtain 900 mg' of a white oily substance.

This product had the following physical properties and was identified as 3-[p-(#-M-acetylaminocaproyl)phenyl]globion methyl ("tstl").

NMR (ODOML # (ppm) Near, 85 (2
H, d, J=&SH+g, benzene IIH8).

t, zs (zH,a, J-&5H1l, penzey
jJIH′s ) +ha<sH,e, CHI −
3-0-).

! 2-15 (81, m, OHt).

LO5 (su, s, CHI-6-N).

13-L8 (6H, m, CHl).

Example table Synthesis -N-acetylaminocapric acid chloride S-OO
η was suspended in carbon disulfide 2-OdK, aluminum chloride tt was added under water cooling with vigorous stirring, and then 374 η of phenyglobionic acid methyl ester and 1 carbon disulfide were added.
9. Add the solution with 0 m and react under reflux for &s hours. After the reaction was completed, the solvent was distilled off, water was added to the residue, and the mixture was extracted with lyaloform. The five chloro-7-ol layers were treated according to a conventional method, and the resulting residue was purified by column chromatography (elution solvent: ri-c107-olm) to obtain the desired product.
s) s4ssp (yield: @I) was obtained.

This material has the following physical properties and supports the structure.

NMR (ODOM) + J (ppm) 7.85 (2H, d, J-JL5Hz, benzene ring H8
).

y, zs(za, a, J-asaz, penzea m! Ha
).

36 (3H, a, 0Hs-6-〇-).

L3-15 (18H, m, methylene).

2.0 (3H,s,0Hs-δ-N-).

Example 1 3Cp-(aa-N-acetyla Z obtained in Example 4)
nooctanoyl)phenyl] pion-methyl (16
5) 300 m+9 was treated and purified in the same manner as in Example 2 to obtain the desired (is*) z 2 t mg (yield: '
IQ-) was obtained.

This material has the following physical properties and supports the structure.

mMR(MeoH-aaL #(ppm):?, 11
5 (!H, tl, J simple & 5Hg, benzene ring H8).

'1.32 (211, tl, J-IL5Hg, Benzene 1IH8).

10-λ2 (18H, m, methylene).

Example 400 μl of 1-acetylaminovaleryl acid chloride was suspended in carbon disulfide, and aluminum chloride IP was added under water cooling with vigorous stirring, followed by phenylpropion.
A solution of 369 ml of methyl ester and 5 d of carbon disulfide was added and reacted under reflux for 2 hours. Thereafter, it was treated in the same manner as in Example 4, and the desired product (162) a s t■ (yield: 5
2-) was obtained.

This material has the following physical properties and supports the structure.

NMR (aDem) + '(ppm) Near, 115
(!H, +1,, T-&5Hg, benzene ring Hs)
.

y, zs (za, a,, y-asa+, penze/1lHa) 1♀ 14i6 (3H, II, CHs O).

to~13 (12H, Otori, methylene).

10 (3H, ts, OHs Q MH).

Synthesis of Example 7 4-M-acetylaminomethylbenzoic acid chloride LOf, prepared by reacting 4-M-acetylaminomethylbenzoic acid with thionyl chloride, was suspended in sowty carbon disulfide and cooled with water while stirring vigorously. Aluminum chloride L
After adding if, a solution of 776 μm of phenylpropionate methyl ester and tOd of carbon disulfide was added, and the mixture was stirred under reflux for 4 hours. After the reaction is complete, the carbon disulfide layer is separated by decandation, and a small amount of ice water is carefully added to the residue to decompose excess aluminum chloride. Then with ethyl acetate 3
Extracted twice.

The ethyl acetate layer was washed with an aqueous INN sodium hydride solution, then water, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 42 cm of yellow oil.

This substance has the following physical properties and was identified as (136).

MMR (ODOts) + J (ppm): '1.2~
7.8 (II H, m, benzene IIHII) 11
g(2H@(1, Jsm6Hz, NHOHt
) 11 g (3H, s, CHs-6-〇-).

2.4~&2 (4H, m, OHt).

− ! 0(3H,a,Cμ--N).

Examples & 4-N-acetylaminomethylbenzoin-chloride LOf
was suspended in 3s- of carbon disulfide, stripped, and 20f of aluminum chloride was added under water cooling with stirring, followed by phenylacetic acid methyl ester? (111■ and carbon disulfide xsw
A solution of j was added and stirred under reflux for 4 hours.

Thereafter, the same treatment as in Example 7 was carried out to obtain the desired compound (142) 753■ (yield: 49) having the following physical properties.

NMR (CD0ta), -(ppm) near, 1~
7.9 (8H, m, benzene jJIIIs).

4 (2H, (1, J-6Hg, -NH-OHt
−).

16 (3H, a, OHs -3-o-).

155 (2H18T Cut) +♀ zo(an, B, OHs ON).

Patent applicant Teijin Ltd.

Claims (1)

[Scope of Claims] L An azunocarbonate derivative or a salt thereof represented by the following formula [1] 3 (or an acyl group having 1 to 6 carbon atoms). 2 The aminocarmine Shun derivative or its salt according to claim 1, represented by the following formula [1)-a. 1. The aminocarminic acid trout conductor or its salt according to claim 2, wherein R1 in the above formula [1] -a is an acetyl group. The aminocardic acid derivative or its salt according to claim 2 or 3, wherein xl in the above formula [1] -a is a methylene group or a methylene group, and R4 is -1:joOR'. Gourd The following formula [■] RIMHOHt X' Co Hat
” ・ Aminocarboxylic acid halide represented by [1] and the following formula [厘] 6zl-R4I ・・・・・・・・・・・・ [1
The following formula ct]-a 1 R'MHOH* I, which is characterized by subjecting the compound represented by 3 to an acylation reaction in the presence of a Lewis acid, and then subjecting it to hydrolysis and/or salt-forming reaction as necessary. '0-O-X'R'・
... [I] a [in the formula, R', ! ", X-value and R' are the same as defined above." A method for producing an aminocarbon tall I4 body or its salt represented by the following formula CI]-!L R'1iHOHt X"c-O-x-R'・
... [13a [wherein, R', X', 14 and R
4 is the same as the above definition. ] A 72-N phosphoric acid derivative or a salt thereof is represented by the following formula [fl M'(R') number-zBH4...[W] 4I reduction and then, if necessary, hydrolysis and/or salt formation reaction.
The following formula [1] R'NH foil-xl-aH-Q-x
"-R1----[1]-b [wherein, R1,!',
l' and r are the same as defined above. ] A method for producing an aminocarboxylic acid derivative or its salt.