JPH11302250A - Production of n,n'-diacylcystine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound having immunoregulation activity and useful as a therapeutic medicine for various diseases such as chronic bronchitis by treating a specific compound in the presence of an organotin compound. SOLUTION: An esterified N,N'-diacylcystine compound represented by formula I [R<1> and R<2> are each an alkyl, a cycloalkyl or the like; R<3> is a primary or secondary alkyl, aryl or the like] is treated in the presence of an organotin compound to provide the objective compound of formula II in which R<3> is eliminated. Furthermore, a compound represented by formula III (R<4> to R<6> are each a lower alkyl, a cycloalkyl or the like), e.g. bis(tricyclohexyltin) oxide is preferably used as the organotin compound and e.g. diethyl ether is used as the solvent and the reaction is preferably carried out in a range of cold temperature to boiling point of each solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for various diseases such as chronic bronchitis and rheumatoid arthritis, which has immunomodulatory activity (JP-A-4-230359, JP-T-5-5077).
The present invention relates to a method for producing an N, N'-diacylcystine compound or a salt thereof, which can be used in the above (5).

[0002]

2. Description of the Related Art Conventionally, N, N'-diacylcystine compounds have been prepared by the following methods: (1) hydrolysis of diester, (2) oxidative coupling of cysteine, and (3)
Methods for direct acylation of cystine are known.

(1) Hydrolysis method of diester compound

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In this method, compound 1 is obtained by hydrolyzing compound 2 under basic conditions. However, the elimination reaction of β-position of esterified carboxylic acid 2 proceeds simultaneously, and C- With cleavage of S bond, [3A] [4A]
[4B] There was a problem that [3B] was produced as a by-product and the yield of the target compound 1 was reduced.

Further, under basic conditions, a disproportionation reaction accompanies, and in the case of an asymmetric compound in which R ¹ ≠ R ² , the yield of the target compound 1 further decreases (M. Bodanszky and J. Ma
rtinez, Synthesis 1987, p.333-349).

(2) Oxidative coupling of cysteine

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In this method, the target compound 1 is obtained by oxidatively coupling the corresponding non-esterified N-acylcysteine [5A] [5B]. However, when synthesizing the asymmetric target compound 1 in which R ¹ ≠ R ² , three kinds of mixtures [1] are usually used.
As a result of the formation of [1 ′] and [1 ″], the yield of the target compound 1 decreases, and it is extremely difficult to separate and purify the target compound 1 from the mixture by HPLC or the like. (EP463514).

(3) Method for direct acylation of cystine In this method, cystine is directly acylated to obtain the desired compound 1
Is not suitable for the synthesis of an asymmetric target compound 1 in which R ¹ ≠ R ^2. For example, even if the target compound 1 is produced, the oxidation coupling method of the above (2) can be used. Similarly, there was a problem that separation / purification of the target compound 1 was extremely difficult.

[0009]

An object of the present invention is to solve the above-mentioned problems of the conventional method and to obtain an N, N'-diacylcystine compound in high yield.

[0010]

According to the present invention, there is provided a compound of the formula (I)

[0011]

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(Wherein R ¹ and R ² are the same or different and each represents an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aryl group, an aralkyl group, a protected amino acid residue, Represents a cyclic group, and R ³ represents a primary or secondary alkyl group, an aryl group or a heterocyclic group, and represents R ¹ , R ² and R ³ described above.
Each of which may be unsubstituted or substituted) is treated with an esterified N, N′-diacylcystine compound in the presence of an organotin compound to remove R ^3. II)

[0013]

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(Wherein R ¹ and R ² are the same as described above), and a process for producing an N, N'-diacylcystine compound or a salt thereof.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The alkyl group represented by R ¹ and R ² includes lower primary alkyl groups such as methyl, ethyl, propyl, n-butyl, isobutyl, n-pentyl and 3,3-dimethylbutyl; Isopropyl, sec-
Lower secondary alkyl groups such as butyl and 2-pentyl, t
Straight or branched chain alkyl groups such as lower tertiary alkyl groups such as -butyl; cycloalkyl groups include cyclopentyl, cyclohexyl and the like;
Alkenyl groups include allyl, propenyl, isopropenyl and the like; cycloalkenyl groups include
Cyclopentenyl, cyclohexenyl and the like;
Alkynyl groups include 1-propynyl, 2-propynyl and the like; aryl groups include phenyl, naphthyl and the like; aralkyl groups include benzyl, phenethyl and the like.

The protected amino acid residue means a group having a structure obtained by removing a carboxyl group from a protected amino acid or a peptide; amino acids of the amino acid residue include glycine, alanine, valine, leucine and isoleucine. Such as aliphatic amino acids, oxyamino acids such as serine and threonine, sulfur-containing amino acids such as cysteine, cystine and methionine, acidic amino acids such as aspartic acid and glutamic acid, amide amino acids such as asparagine and glutamine, and bases such as lysine, arginine and ornithine Acidic amino acids, aromatic amino acids such as phenylalanine and tyrosine, heterocyclic amino acids and peptides such as histidine, tryptophan and proline;
Examples of the protecting group include those commonly used as described in, for example, Basics and Experiments of Peptide Synthesis (Nobuo Izumiya, Maruzen (1985)), that is, acyl, benzyl, arylsulfonyl (tosyl), tertiary alkoxycarbonyl And protecting groups for carboxyl groups such as benzyloxy and tertiary butyloxy. Examples of the heterocyclic group include oxygen, sulfur and nitrogen such as furyl, thienyl, pyrrolyl and piperidyl.
And a 6-membered heteromonocyclic.

The primary or secondary alkyl group, aryl group and heterocyclic group in R ³ include the above-mentioned R ¹
And the same as these groups in R ² .

The groups R ¹ , R ² and R ^{3 in} the above groups may be unsubstituted or substituted, and the substituents of the alkyl, alkenyl and alkynyl groups in R ¹ and R ² and the substituents in R ³ Examples of the substituent of the alkyl group include nitro, hydroxy, oxo, thioxo, cyano, carbamoyl, carboxyl, alkoxycarbonyl, sulfo, halogen, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, amino, acylamino, alkyl amino,
Selected from tertiary alkoxycarbonylamino, alkanoyl, cycloalkyl, aralkyl, unsubstituted or substituted aryl and heterocyclic groups; the cycloalkyl group, cycloalkenyl group, aryl group, aralkyl group in R ¹ and R ² , The substituent of the amino acid residue and the heterocyclic group, and the substituent of the aryl group and the heterocyclic group in R ³ are selected from the above substituents and unsubstituted or substituted alkyl.

Preferred compounds of formula (II) are R ¹ and R
² is the same or different; (1) an unsubstituted alkyl group; (2) halogen, alkoxy, unsubstituted aryl, aryl-substituted aryl, aralkyl-substituted aryl, tertiary alkoxycarbonylamino, alkylthio, acylamino, heterocyclic group and An alkyl group substituted with a group selected from cycloalkyl; (3) a cycloalkyl group; (4) an unsubstituted aryl group; (5) nitro, hydroxy, cyano, carboxyl, alkoxycarbonyl, halogen, alkoxy, amino,
An aryl group substituted with a group selected from acylamino, alkylamino, tertiary alkoxycarbonylamino, alkanoyl, aryl and aralkyl; or (6) a protected amino acid residue, wherein R ³ is unsubstituted primary. Alternatively, the compound is a secondary alkyl group, an aryl-substituted primary or secondary alkyl group, an unsubstituted aryl group, or an oxygen-containing or sulfur-containing 5- to 6-membered heteromonocyclic group.

Further preferred compounds of the formula (II) are those wherein R ¹ and R ² are the same or different and are (1) an unsubstituted lower alkyl group; (2) an aralkyl group; (3) an aralkyl-substituted aralkyl group; An amino acid residue protected with a lower tertiary alkoxycarbonyl group, an acyl group or an arylsulfonyl group; (5) a cycloalkyl-substituted lower alkyl group; (6) an unsubstituted phenyl group or an aryl-substituted phenyl group; A carbonylpiperidyl group; or (8) a thienyl group or a furyl group; wherein R ³ is an unsubstituted lower primary or secondary alkyl group or a phenyl substituted lower primary or secondary alkyl group. .

R ³ is preferably methyl, ethyl, propyl or benzyl.

The objective compound (II) and the starting compound (I) of the present invention include optically active substances. According to the present invention, when the optically active substance is used as the starting compound (I), racemization occurs. The optically active target compound (II) can be obtained without performing the above.

The N, N'-diacylcystine compound (I) which is a starting compound in the method of the present invention is produced by the following method.

A The symmetrical starting compound (I) wherein R ¹ = R ² is described, for example, in J. Am. Chem, Soc., Vol. 79, p.
4544 (1957) and J. Chem. Soc., 3638-3644 (1964). b (i) The asymmetric starting compound (I) wherein R ¹ ≠ R ² is produced, for example, according to the method described in JP-A-4-230359. (Ii) The asymmetric starting compound is also produced by the following method.

[0025]

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Step A is the protection of the amino group using a conventional protecting group such as a benzyloxycarbonyl group. B
The step is an esterification step in which a halide (R ³
X) or an alcohol (R ³ OH). Steps C and E are N-acylation steps, which are carried out by conventional means using carboxylic acids (R ¹ COOH, R ² COOH) or their reactive derivatives (acid halides, acid anhydrides, active esters). Step D is deprotection of a protecting group such as a benzyloxycarbonyl group, and is performed by a conventional means.

The above steps A and D are described above.
J. Am. Chem, Soc., J. Chem, Soc.,
TW Geene "Protection Groups in Organic Synthesi
s "John Wiley & Sons, Inc. (1991), and for Steps B, C and E, RC
Larock "Comprehensive Organic Transformations, AGu
ide to Functional Group Preparations "VHC Publisch
ers, Inc. (1989).

Examples of the organotin compound include the following a) to e)
What is selected from is used.

[0029]

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(Wherein, R ^{4 to} R ¹⁴ are the same or different and each represent a lower alkyl group, a cycloalkyl group, an aryl group or a halogen atom, and Y ^{1 to} Y ⁴ are the same or different and each represent a hydroxy group Or represents an alkoxy group)

Examples of the organotin compound (a) include bis (tricyclohexyltin) oxide, bis (cyclohexylalkyltin) oxide, bis (triphenyltin) oxide, bis (chloro-di-n-butyltin) oxide, Bis (dichloro-n-butyltin) oxide, bis (chloro-diphenyltin) oxide, bis (dichloro-phenyltin) oxide,
Bis (trimethyltin) oxide, bis (tri-n-
(Butyltin) oxide.

Examples of the organic tin compound (b) include di-n-butyltin oxide and diphenyltin oxide.

Examples of the organotin compound (c) include trimethyltin hydroxide, triphenyltin hydroxide, tri-n-butyltin methoxide, tributyltin ethoxide, and triphenyltin methoxide.

Examples of the organotin compound (d) include methylstannoic acid and phenylstannoic acid.

Examples of the organotin compound (e) include dibutyltin dimethoxide.

In the production method of the present invention, the reaction is carried out in the presence or absence of a solvent. As the solvent, ether solvents such as diethyl ether, dimethoxymethane and dioxane; hydrocarbon solvents such as benzene, toluene and xylene; and inert solvents such as acetonitrile are used alone or in combination.

The reaction can be carried out at a temperature ranging from the time of cooling to the boiling point of each solvent. The reaction without a solvent can be carried out at a temperature lower than the boiling point of the organotin compound.

In the present specification, the alkyl, primary alkyl and alkoxy have 1-20 carbon atoms; lower alkyl, lower primary alkyl and lower alkoxy have 1-6 carbon atoms; Carbon number 3-20; lower secondary alkyl carbon number 3-6; tertiary alkyl carbon number 4-20; lower tertiary alkyl carbon number 4-6
Alkenyl and alkynyl have 2 to 20 carbon atoms;
Cycloalkyl and cycloalkenyl have 3 to 8 carbon atoms.
However, the aryl preferably has 6 to 14 carbon atoms.

Examples of the acyl include alkylcarbonyl such as formyl, acetyl and propionyl, arylcarbonyl such as benzoyl, aryl-substituted alkylcarbonyl, heterocyclic carbonyl, carbamoyl and the like.

[0040]

Embodiment 1

[0041]

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To a solution of compound 1a in 493 mg (1.0 mmol) / toluene (40 ml) was added (n-Bu ₃ Sn) ₂ O 5.
96 g (10.0 mmol) were added, and 1
The mixture was heated to 00 ° C and stirred. After 22 hours, toluene was distilled off, and the residue was mixed with 50 ml of a 10% KF solution and 50 ml of ethyl acetate.
Was added and stirred vigorously for 30 minutes. The water layer was separated by removing the decomposed tin compound. The water bath was acidified with 10% HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried, and the solvent was distilled off. The residue was recrystallized from ethyl acetate-hexane to give 398 mg (yield 91%) of colorless crystals 2a.

Embodiment 2

[0044]

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By treating in the same manner as in Example 1, compound 2b (90% yield) was obtained from compound 1b.

Embodiment 3

[0047]

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Compound 1c 350 mg (0.83 mmol) /
(N-Bu ₃ Sn) ₂ O was added to a toluene (25 ml) solution.
4.9 g (8.2 mmol) were added, and 1 under an argon atmosphere.
Stirred at 00 ° C. overnight. The reaction solution was concentrated, and the precipitated tin-ester was collected by filtration and washed with ethyl ether. This was dissolved in 20 ml of water-20 ml of ethyl ether containing 2 ml of acetic acid and stirred vigorously for 1 hour. The aqueous layer was separated, washed with ethyl ether, and then water and acetic acid were distilled off under reduced pressure to obtain 259 mg of compound 2c (yield: 85%).

Embodiment 4

[0050]

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By treating in the same manner as in Example 3, compound 2d was obtained from compound 1d (yield 90%).

Examples 5 to 10 In the same manner as in Example 1, the compounds shown in Table 1 below are obtained.

[0053]

[Table 1]

Reference Example 1

[0055]

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Under ice cooling, 2.9 g of compound 3 (6.14 mm
ol) / acetic acid (40 ml), a 25% HBr acetic acid solution (29 ml) was added dropwise, and the mixture was stirred for 70 minutes. 300 ml of ethyl ether was added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. Ethyl ether was removed by decantation, and H
Br-acetic acid and ethyl ether were removed. The obtained residue was dissolved in 150 ml of dichloromethane, and 949 mg (6.75 mmol) of benzoyl chloride / CH ₂ Cl ₂ (1
5 ml) solution was added dropwise, and then 1.75 g (13.51 mmol) of diisopropylethylamine / CH ₂ Cl ₂ (15
ml) The solution was added dropwise, and the temperature was gradually raised to room temperature. Ice water was added to the reaction solution, the organic layer was separated, washed with water, dried, the solvent was distilled off, and the residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate = 3: 7) to give compound 1b. 1.22 g (45% yield from compound 3) was obtained.

Reference Example 2

[0058]

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By treating in the same manner as in Reference Example 1, compound 1c (43% yield from compound 3) was obtained.

Claims (6)

[Claims] 1. A compound of the formula (I) (Wherein R ¹ and R ² are the same or different and each represents an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aryl group, an aralkyl group, a protected amino acid residue or a heterocyclic group. Wherein R ³ represents a primary or secondary alkyl group, an aryl group or a heterocyclic group, and the above groups R ¹ , R ² and R ³ may be unsubstituted or substituted The N, N'-diacylcystine compound esterified by the formula (II) is treated in the presence of an organotin compound to remove R ^3. (Wherein R ¹ and R ² are the same as described above)
A method for producing an N'-diacylcystine compound or a salt thereof. ^2. The alkyl, alkenyl and alkynyl substituents in R ¹ and R ² and the alkyl substituent in R ³ are nitro, hydroxy, oxo, thioxo, cyano, carbamoyl, carboxyl,
Alkoxycarbonyl, sulfo, halogen, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, amino, acylamino, alkylamino, tertiary alkoxycarbonylamino, alkanoyl, cycloalkyl, unsubstituted or substituted aryl and heterocyclic R ¹ and R
^{In 2} , a cycloalkyl group, a cycloalkenyl group,
The aryl group, an aralkyl group, a protected amino acid residue and a substituent of a heterocyclic group, and the substituent of the aryl group and the heterocyclic group in R ³ are, in addition to the above substituents, unsubstituted or substituted alkyl. The method of claim 1, which is selected. 3. R ¹ and R ² are the same or different,
(1) an unsubstituted alkyl group; (2) a group selected from halogen, alkoxy, unsubstituted aryl, aryl-substituted aryl, aralkyl-substituted aryl, tertiary alkoxycarbonylamino, alkylthio, acylamino, heterocyclic group and cycloalkyl (3) cycloalkyl group; (4) unsubstituted aryl group; (5) nitro, hydroxy, cyano, carboxyl, alkoxycarbonyl, halogen, alkoxy, amino,
An aryl group substituted with a group selected from acylamino, alkylamino, tertiary alkoxycarbonylamino, alkanoyl, aryl and aralkyl; or (6) a protected amino acid residue, wherein R ³ is unsubstituted primary. The method according to claim 1, which is a secondary alkyl group, an aryl-substituted primary or secondary alkyl group, an unsubstituted aryl group, or an oxygen-containing or sulfur-containing 5- to 6-membered heteromonocyclic group. 4. R ¹ and R ² are the same or different and are (1) unsubstituted lower alkyl group; (2) aralkyl group; (3) aralkyl-substituted aralkyl group; (4) lower tertiary alkoxycarbonyl group An amino acid residue protected with an acyl group or an arylsulfonyl group; (5) a cycloalkyl-substituted lower alkyl group; (6) an unsubstituted phenyl group or an aryl-substituted phenyl group; (7) a lower alkoxycarbonylpiperidyl group; ) A thienyl group or a furyl group; wherein R ³ is an unsubstituted lower primary or secondary alkyl group or a phenyl substituted lower primary or secondary alkyl group.
The manufacturing method described. 5. The method according to claim 1, wherein R ³ is a methyl group, an ethyl group, a propyl group or a benzyl group. 6. The method according to claim 1, wherein the organotin compound is selected from a) to e). Embedded image (Wherein, R ^{4 to} R ¹⁴ each represent a lower alkyl group, a cycloalkyl group, an aryl group, or a halogen atom;
^{1 to} Y ⁴ each represent a hydroxy group or an alkoxy group)