JPS641466B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel N,S-disubstituted (R)-cysteine derivatives, and in particular the general formula (): [In the formula, R ^a ₁ represents a hydrogen atom or a group R ₁ -CO-, where R ₁ is a C ₁₁ to C ₂₁ -alkyl group, a C ₁₇ -
It is an alkenyl group or a 7-(2-octyl-cyclopropyl)-heptyl group, and R ₂ is C ₁₁ to C ₁₇
- an alkyl group, and R ₃ is hydrogen or a palmitoyloxymethyl group. The asymmetric centers indicated by * and ** have the above-mentioned configuration] and ** mixtures of epimeric R- and S-compounds on the carbon atom, and further relate to salts thereof.

Lipopeptides have already been described in the literature as degraded fragments of lipoproteins. i.e. Hankte and Braun (Er. J. Biochem, 34 ,
284-296 (1973) isolated an impure lipopeptide or lipopeptide mixture by enzymatic degradation from murein-lipoproteins of the outer cell wall of Escherichia coli; Structural formula of (): (wherein Y ₁ , Y ₂ and Y ₃ are acyl groups of different higher saturated or unsaturated fatty acids, e.g. carbon atoms 14
~19 acyl groups such as fatty acids) and corresponding formulas with shorter polypeptide chains. Although this structure is the basis of the murein protein (see the above-mentioned literature), the absolute configuration of the bisymmetric carbon atoms in the above formula has not been studied. Murein lipoprotein and its degradation products exhibit mitotic reproductive effects in vitro on murine lymphocytes [Z. Immun.--Forschung,
See Vol. 153, pp. 11-22 (1977)].

As is clear, the formula (): Glycerylcysteine is based on a degraded lipopeptide derived from murein protein. These fragments are not products whose composition is well defined as products of enzymatic degradation of natural products, but are clearly complex mixtures of condensation products of said peptide moieties and very different acyl derivatives of glycerylcysteine. be.

The lipopeptide described in Japanese Patent Application No. 53-073828 (Japanese Unexamined Patent Publication No. 54-9224) differs from the above-mentioned degradation products of murein protein in many respects. Thus, this lipopeptide is a lipopeptide of a single, precisely defined chemical composition and configuration, obtained synthetically, and therefore suitable for therapeutic use. The group of compounds constituted by this lipopeptide has an erythritol group in place of the glycerin moiety in "glycerylcysteine" and/or a different amino acid sequence or Compounds in which only one amino acid is present instead, and derivatives such as amides or esters of a terminal carboxyl group are included.

The compounds of the present invention may be used as such or as disclosed in the patent application.
It can be used as a starting material for the lipopeptide described in JP-A No. 53-073828 (Japanese Unexamined Patent Publication No. 54-9224).

The acyl group R ₁ CO in the compound of general formula () is a saturated or unsaturated fatty acid, such as myristic acid,
Those derived from palmitic acid, margaric acid, stearic acid, arachidic acid, oleic acid, elaidic acid, linoleic acid, α- and β-eleostearic acid, stearolic acid, α-linolenic acid, or dihydrosteruclic acid It is. Preferred acyl groups are those having 14 to 18 carbon atoms. The acyl group R ₂ CO is, for example, one derived from lauric acid, myristic acid, palmitic acid, margaric acid or stearic acid.

In the compound of general formula () or its diastereomeric mixture and its salt or complex, the group
R ₁ and R ₂ may be the same or different from each other. 3 or 4 acyl groups are identical and in particular this is a palmitoyl group,
Compounds that are stearoyl or oleoyl groups are preferred.

An important group of compounds of the invention has the general formula (): (In this formula, R ₁ and R ₂ have the above-mentioned meanings.) Compounds in which the acyl groups R ₁ CO and R ₂ CO are the same and are palmitoyl or stearoyl groups, and R ₁ CO
and R ₂ CO is different, for example palmitoyl, stearoyl or oleoyl,
Mention may in particular be made of all compounds such that these radicals appear in any combination and/or variation as indicated in the table below. Here, the glycerylcysteine compound is N-acyl-O-O-
Diacyl-Cys is abbreviated. N-palmitoyl-OO-dipalmitoyl-Cys-OH N-stearoyl-OO-distearoyl-Cys
-OH Compounds with different acyl groups on the N- and C-atoms of glycerylcysteine include: N-myristoyl-OO-dipalmitoyl-Cys
-OH N-Lauroyl-OO-Dipalmitoyl-Cys-
OH N-stearoyl-OO-dipalmitoyl-Cys
-OH.

The second group of compounds according to the present invention [group] includes compounds in which the arrangement of the C ^** atom in the general formula () is S instead of R, and R- and S-
Mixtures of diastereomers, such as those obtained during synthesis. Also in this group, special types and compounds are those specifically mentioned in the R group [general formula ()].

The third group of compounds of the present invention has the general formula () in which R ₃ is C ₁₅ H ₃₁ —CO—O—CH ₂ —
radicals, in which the configuration at the C ^** atom is R or S, and in particular includes diastereomeric mixtures. Its subgroup is the general formula (): and in particular R- at the C ^** atom
It has an arrangement. Acyl group R ₁ CO— and
R ₂ CO-- are preferably the same, especially palmitoyl group, stearoyl group or, in the case of R ₁ CO--, oleoyl group. However, all combinations and/or variations can be made as mentioned above for other groups.

Specific compounds are, for example, those shown in the table above as specific compounds of the group, where N-acyl-O-O-acyl-Cys is an erythritylcysteine group rather than a glycerylcysteine moiety as described above. It is a compound.

The novel compounds of the invention are acids and form salts with bases, such as ammonium salts, salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium.

General formula () of the present invention in which R ^a ₁ is a group R ₁ -CO-
The compounds represented by, salts thereof, and mixtures thereof exhibit valuable pharmacological properties, particularly excellent immunostimulatory activity, and this activity was demonstrated in vitro in Japanese Patent Application No. 53-073828 (Japanese Patent Application Laid-Open No. 54-9224). Public bulletin)
occurs in similar amounts to the compounds described in .

The immunoenhancing effect of the compound of the present invention represented by the general formula () in which R ^a ₁ is a group R ₁ --CO, salts thereof, and mixtures thereof can also be demonstrated in vivo.

NMRI mice are immunized by intraperitoneal injection of 10 μg/day of non-precipitated BSA. Serum samples are taken after 9, 15 and 29 days and tested for anti-BSA antibody content by passive hemagglutination technique. Soluble BSA at the doses used is a co-immunogen to the treated animals. That is, they do not produce antibodies or only produce them in very small amounts. Additional treatment of mice with certain immune-enhancing substances before or after challenge increases the antibody titer in the serum. The effect of the treatment is the result obtained, namely bleeding for 3 days.
It is expressed by the sum of log titer differences. In this test, a compound of the general formula (), a salt or a complex or a mixture thereof, in which R ^a ₁ is the group R ₁ -CO-, was administered for 5 days before or after immunization with BSA.
Antibody production against BSA can be significantly enhanced when doses of ~3 mg/Kg of the substance are administered intraperitoneally or subcutaneously.

Therefore, the compound of the formula () of the present invention in which R ^a ₁ is a group R ₁ --CO-- can be used as described in Japanese Patent Application No. 53-073828 (Japanese Unexamined Patent Publication No. 54-9224). It can also be used as an adjuvant for the claimed compounds. Furthermore, like the compound in which R ^a ₁ is a hydrogen atom, this compound can be prepared according to the method described in Japanese Patent Application No. 53-073828 (Japanese Unexamined Patent Publication No. 54-9224). It can also be used as a starting material for the preparation of the claimed compounds.

The lipopeptides of the invention can be made by methods known per se or by the methods described herein.

Compounds of formula () in which R ₃ is hydrogen are obtained as follows: Starting from 1.1,5.6-D-mannitodiacetonide, 2-O,3-O-isopropylene oxide is obtained by periodate oxidation. Ridden-D-
Glyceraldehyde is obtained, the aldehyde group is reduced to a carbinol group, and this is esterified with P-toluenesulfonic acid. The 1-O-tosyl-2(R)-O,3-O-isopropylidene glycerol thus obtained is condensed with N-acyl-(R)-cysteine in the presence of a basic agent such as potassium carbonate, thus N -Acyl-S- [2(R), 3-
Isopropylenedioxypropyl]-(R)-cysteine is obtained which is saponified with an acid such as acetic acid. Thus obtained N-acyl-S-[2(R), 3
-dihydroxypropyl]-(R)-cysteine can be optionally used to prepare a compound of formula () in which R ^a ₁ is not hydrogen, preferably for example a trimethylsilylethyl group or preferably a benzhydryl ester group or a It is possible to protect the carboxyl group in advance with another carboxyl protecting group described in JP-A No. 073828 (Japanese Unexamined Patent Publication No. 54-9224) and further acylate it at the 2- and 3-positions of the glycerin moiety. .

N-acyl- _or N,O _, O,O- _tetraacyl -S-(2,3,4 _- trihydroxybutyl )--Cysteine can be produced in the same manner as in Example 5.

This acylation is carried out by methods known per se, for example by reaction with a reactive functional derivative of the acid corresponding to the group to be introduced, such as an anhydride or an acid halide, preferably in the presence of a tertiary base such as pyridine or collidine. This can be done by

This method is particularly suitable for producing a compound in which the acyl group in the glyceryl group or erythrityl group and the acyl group in the cysteine group in the general formula () are different.

The obtained compound of formula () can be converted into its salt by methods known per se, for example by reacting the obtained acidic compound with an alkali metal hydroxide or an alkaline earth metal hydroxide. .

Because of the close relationship between the free form of the compounds of the invention and their salt forms, what is said herein with respect to the free compounds may also apply to the corresponding salts. It is something.

The isomer mixtures obtained can be separated in known manner, for example by chromatography and/or fractional crystallization, according to the differences in the physicochemical properties of the components. It is advantageous to isolate the effective isomer.

The process is carried out according to known methods, in the presence or preferably in the absence of diluents or solvents, if necessary with cooling or heating, and under elevated pressure (or) in an atmosphere of an inert gas, for example nitrogen. In this case, attention is paid to all substituents present in the molecule and, if necessary, reaction conditions, especially in the presence of easily hydrolyzed O-acyl groups,
For example, short reaction times, use of low stoichiometric proportions of mild acidic agents, selection of appropriate catalyst, solvent, temperature and/or pressure conditions should be used.

The invention particularly relates to starting compounds for the production of lipopeptides which are described as being of particular value in Japanese Patent Application No. 53-073-828 (Japanese Patent Application No. 54-9224).

The present invention will be explained in more detail with reference to the following examples, but these examples are not intended to limit the scope of the present invention. Each signal in the example has the following meaning.

Z=carbobenzoxy group, ^BUt =tertiary butyl ether group, ^OBut =tertiary butyl ester group, BOC=tertiary butoxycarbonyl group, DMF=dimethylformamide, ONp=p-nitrophenyl ester, HOBt=N- Hydroxybenzotriazole, DC = thin layer chromatography.

In thin layer chromatography, silicic acid gel was used as an adsorbent and the following system was used as a developing agent.

System 3: Acetic acid-pyridine-water (65:20:15).

System 157: Chloroform-methanol-water-acetic acid (70:42:10:0.5) System 157c: Chloroform-methanol-water-acetic acid (75:25:5:0.5).

Example 1 N-palmitoyl-S-[2(R),3-dihydroxypropyl]-(R)-cysteine can be made as follows: N-palmitoyl-(R)-cysteine 13.9
g, potassium carbonate 5.5 g and 1-O-tosyl-
15 g of 2(R)-O-3-O-isopropylidene glycerin was added to 250 ml of ethanol in a nitrogen atmosphere.
Heat at 80℃ for 8 hours. The reaction mixture obtained after evaporation is purified by chromatography on 400 g of Merck silicic acid gel, eluting first with chloroform/acetone (8:2) and then with chloroform/methanol (8:2). . The potassium salt of N-palmitoyl-S-[2(R),3-isopropylidenedioxypropyl]-(R)-cysteine is thus obtained, which is heated to 80° C. for 4 hours in 80% aqueous acetic acid. Saponify by. Evaporate to dryness and dissolve the residue in chloroform.
Shake with water. After drying and evaporating the chloroform phase, a colorless residue is obtained, which is recrystallized from cyclohexane and N-palmitoyl-S-
[2(R), 3-dihydroxypropyl]-(R)
- Cysteine is obtained. Melting point 110℃, [α] ²⁰ _D =
−25° (c=0.9, in MeOH).

N-palmitoyl-(R)-cysteine can be produced as follows.

Suspend 45 g (0.37 mol) of (R)-cysteine in 350 ml of pyridine and stir well at room temperature in a nitrogen atmosphere with 140 ml of palmitic acid chloride.
(1.67 eq.) in 550 ml of methylene chloride dropwise. After stirring for 20 hours, acidify with 2N hydrochloric acid.
Partition between chloroform and water. After drying and evaporating the chloroform phase, a crystalline mixture consisting of approximately 1/3 dipalmitoylcysteine and approximately 2/3 monopalmitoylcysteine is obtained. hot acetone 1
and from which a 1:1 mixture of di- and mono-palmitoylcysteine is crystallized. N-palmitoylcysteine is obtained from this acetone solution by evaporation and is recrystallized from benzine. Melting point 65-67℃, [α] ²⁰ _D = +1° (c =
0.8, methanol).

A mixture of di- and mono-palmitoylcysteine is treated in methanolic solution with 2 ml of concentrated caustic soda solution for 15 minutes at room temperature while adding an aqueous solution of 12 g of sodium sulfite. After evaporation of the methanol and acidification of the residue with 2N hydrochloric acid, chloroform extraction yields the remaining N-palmitoylcysteine, which is likewise recrystallized from benzine.

Example 2 N-palmitoyl-S-[2(R),3-dipalmitoyloxypropyl]-(R)-cysteine and a 2(S)-compound corresponding to this compound (this is abbreviated as 2(R,S)) A diastereomeric mixture with () can be prepared as follows.

6.3 g (2.78 mmol) of N-palmitoyl-S-[2(R),2-dipalmitoyloxypropyl]-(R)-cysteine benzhydryl ester are dissolved in a mixture of 12 ml of trifluoroacetic acid and 48 ml of methylene chloride. After 1 hour at room temperature, the solution is evaporated and the oily residue is triturated with water. The precipitated N-palmitoyl-S-[2(R),3-dipalmitoyloxypropyl]-(R)-cysteine is filtered off with suction, dried and triturated three times with benzine to remove the benzhydrol. When the residue is crystallized from acetone-water, the product has a melting point of 71
Colorless crystals of [α] ²⁰ _D = -1° (dioxane) are obtained at ~75°C.

The above ester is obtained as follows: 12 g (20 mmol) of N-palmitoyl-S-[2(R),3-dihydroxypropyl]-(R)-cysteine benzhydryl ester in 60 ml of pyridine.
and 60 ml of methylene chloride, and 14.5 ml (13.2 g) of palmitic acid chloride are added dropwise at 0-10°C. The reaction is complete by thin layer chromatography after 2 hours at room temperature. 10 ml of methanol are added to the suspension (pyridine hydrochloride) and stirred for 20 minutes at 25°C, then the reaction mixture is further evaporated. The residue is dissolved in chloroform, shaken twice each with 0.5N hydrochloric acid, 10% sodium bicarbonate and water, the chloroform phase is dried over sodium sulfate and evaporated to a syrup. The syrup is chromatographed on silicic acid gel in chloroform to give the pure ester. This chromatographically single fraction (DC in chloroform:acetate (98:2) with silicic acid gel - comparison; Rf = 0.5) is evaporated and recrystallized from acetone. Melting point 69-71℃
Colorless crystals of N-palmitoyl-(S)-[2(R),3-dipalmitoyloxypropyl]-(R)-cysteine benzhydryl ester are obtained.

N-palmitoyl-S-[2] used above
The benzhydryl ester of (R),3-dihydroxypropyl]-(R)-cysteine can be obtained, for example, as follows: N-palmitoyl-S-[2(R),3-dihydroxypropyl]-(R) - Cysteine 23.4g
(54 mmol) in chloroform-acetone mixture 150
ml and to this is added dropwise at room temperature a solution of 13.6 g (70 mmol) of diphenyldiazomethane in 50 ml of chloroform. After 3 hours at room temperature, the initially red solution faded and the reaction was completed by thin layer chromatography (chloroform:methanol=9:1; using silicic acid gel). Evaporate to dryness in vacuo and extract the residue cold with petroleum ether. The residue is filtered through silicic acid gel with methylene chloride as solvent. Colorless crystals of benzhydryl ester with a melting point of 88-91°C are thus obtained.

In order to produce N-palmitoyl-2-[2(R,S),3-dihydroxypropyl]-(R)-cysteine, the following operation is performed.

N-palmitoyl-(R)-cysteine 50g
(139 mmol), 12.4 g of glycide and 45 g of potassium carbonate are heated in 375 ml of ethanol to 80° C. for 16 hours with thorough stirring in a nitrogen atmosphere. After cooling to room temperature, the pH is made acidic to about 4 with 2N hydrochloric acid and water is added. At this time the product precipitates. Filter with suction and wash with water until the filtrate is free of chloride ions. The suction filter cake is dried in vacuo and then recrystallized from acetic ester. N-Palmitoyl-
S-[S(R),3-dihydroxypropyl]-
Colorless crystals of a diastereomeric mixture of (R)-cysteine and N-palmitoyl-S-[2(S),3-dihydroxypropyl] with a melting point of 76-155°C
-(R)-cysteine is obtained.

As mentioned above for the R-compound, N-palmitoyl-S-[2(R,S),3-dihydroxypropyl]-(R)-cysteine was reacted with diphenyldiazomethane and then with palmitic acid chloride. N-palmitoyl-S-[2(R,
S), 3-dipalmitoyloxypropyl]-
(R)-cysteine benzhydryl ester is obtained.

When this diastereomeric mixture (19.8 g) was chromatographed on a column of 250 g of silicic acid gel (Merck) using methylene chloride as a solvent, the ester moiety (1.55 g) contained the R-diastereomer (Rf = 0.61 ; methylene chloride:acetic ester = 98:2, thin layer, silicic acid gel), 12.7 g of R,S-diastereomer mixture in the second part, and S-diastereomer (Rf =
0.53; methylene chloride: acetate ester = 98:2)
1.1g is obtained.

From the (S)-diastereomer, N-palmitoyl-S-[2(S),3-dipalmitoyloxyprol]-(R)-cysteine is obtained as described above; colorless crystals, melting point 64~ 65℃, [α] ²⁰ _D =
+1° (dioxane).

Example 3 The following compounds are prepared analogously to Example 1.

N-Myristoyl-S-[2(R),3-dihydroxypropyl]-(R)-cysteine, melting point
Colorless crystals at 140-150°C; N-stearoyl-S-[2(R),3-dihydroxypropyl]-(R)-cysteine, melting point
Colorless crystals at 140-150°C; N-lauroyl-S-[2(R),3-dihydroxypropyl]-(R)-cysteine, melting point 140
Colorless crystals at ~150°C.

The corresponding benzhydryl esters are, for example: N-myristoyl-S-[2(R),3-dihydroxypropyl]-(R)-cysteine benzhydryl ester, colorless crystals with a melting point of 90-92°C; N -stearoyl-S-[2(R),3-dihydroxypropyl]-(R)-cysteine benzhydryl ester, colorless crystals, melting point 95-97°C; N-lauroyl-S-[2(R),3-dihydroxy Propyl]-(R)-cysteine benzhydryl ester, colorless crystals with a melting point of 95-97°C.

Example 4 The following compounds are prepared analogously to Example 2.

N-lauroyl-S-[2(R),3-dipalmitoyloxypropyl]-(R)-cysteine,
Colorless crystals with a melting point of 70-72°C; N-myristoyl-S-[2(R),3-dipalmitoyloxypropyl]-(R)-cysteine, colorless crystals with a melting point of 71-73°C; N-stearoyl-S- [2(R),3-dipalmitoyloxypropyl]-(R)-cysteine, colorless crystals with a melting point of 74-77°C; N-palmitoyl-S-[2(R),3-dilauroyloxypropyl]-( R) - cysteine,
Melting point 54-56°C; N-palmitoyl-S-[2(R),3-distearoyloxypropyl]-(R)-cysteine, colorless crystals with melting point 82-85°C; N-palmitoyl-S-[2( R),3-dioleoyloxypropyl]-(R)-cysteine,
Colorless oil, chloroform:methanol = 9:1
(Thin layer - silicate gel - Merck) Rf = 0.35; N-palmitoyl-S-[2(R),3-dibehenoyloxypropyl]-(R)-cysteine,
Colorless crystals with a melting point of 87-90℃; N-palmitoyl-S-[2(R),3-di-
(dihydrosterculoyloxypropyl)] -
(R)-Cysteine, colorless waxy substance, Rf=0.38 (N
-same conditions as palmitoyl-2,3-oleoyloxy derivative).

The corresponding benzhydryl ester has the following properties.

N-Lauroyl-S-[2(R),3-dipalmitoyloxypropyl]-(R)-cysteine benzhydryl ester, melting point 65-68°C; Palmitoyloxypropyl-(R)-cysteine benzhydryl ester, melting point 68-70°C; N-stearoyl-S-[2(R),3-dipalmitoyloxypropyl]-(R)-cysteine benzhydryl ester, melting point 70 ~72°C; N-palmitoyl-S-[2(R),3-dilauroyloxypropyl]-(R)-cysteine benzhydryl ester, colorless wax; N-palmitoyl-S-[2(R), 3-distearoyloxypropyl]-(R)-cysteine benzhydryl ester, colorless crystals with a melting point of 80-82°C; N-palmitoyl-S-[2(R),3-dioleoyloxypropyl]-(R) -Cysteine benzhydryl ester, colorless oil; N-palmitoyl-S-[2(R),3-dibehenoyloxypropyl]-(R)-cysteine benzhydryl ester, colorless crystals with a melting point of 85-88°C; N -Palmitoyl-S- [2(R),3-G-
(dihydrosterculoyloxypropyl)] -
(R)-Cysteine benzhydryl ester, colorless wax.

Example 5 N-Palmitoyl-S-2(R), 3(R), 4-
0.9 g of tripalmitoyloxybutyl-(R)-cysteine benzhydryl ester is left in a mixture of 3 ml of trifluoroacetic acid and 12 ml of methylene chloride at room temperature for 2 hours. It is then evaporated to dryness, the residue is triturated with ice water, filtered with suction and the solid is dried. It is then extracted with benzene and recrystallized from acetone. N-Palmitoyl-S- with melting point 76-76.5℃
Colorless crystals of 2(R),3(R),4-tripalmitoyloxybutyl-(R)-cysteine are obtained. Specific optical rotation [α] ²⁰ _D = -5° (c = 0.819, dioxane).

Benzhydryl ester used as a raw material is obtained as follows.

N-Palmitoyl-S-2(R), 3(R), 4-
1 g of trihydroxybutyl-(R)-cysteine benzhydryl ester was mixed with palmitic acid chloride in a mixture of 6 ml of pyridine and 5 ml of methylene chloride.
Acylate with 1.83ml. After 18 hours at room temperature 1 ml of methanol is added and evaporated to dryness. The residue is filtered through 100 g of silicic acid (Merck) with chloroform as solvent. The pure portion by thin layer chromatography (CHCl ₃ :acetic acid ester = 98:2) gives colorless crystals after evaporation with a melting point of 60-62°C.

The raw material for the above reaction is obtained as follows: N-palmitoyl-S-2(R),3(R),4-
Trihydroxybutyl-(R)-cysteine 2.53
g is reacted with 1.37 g of diphenyldiazomethane in a mixture of 12 ml of ethanol and 32 ml of chloroform at room temperature for 15 hours. After evaporation to dryness, the corresponding benzhydryl ester is purified on 150 g of silicic acid gel with chloroform as solvent. Rf=0.3( _CHCl3 :
Acetone = 95:5, silicic acid gel (Merck), thin layer).

N-Palmitoyl-S-2(R), 3(R), 4-
Trihydroxybutyl-(R)-cysteine is obtained as follows: 20 g of N-palmitoylcysteine, 27.6 g of 1-tosyl-2,4-diethylidene-D-erythrite.
and 17 g of caustic potash are stirred in 240 ml of ethanol at 80°C for 15 hours in a nitrogen atmosphere. The salts are then filtered off and the filtrate is evaporated to dryness. Dissolve the residue in 200 ml of H ₂ O:tetrahydrofuran (1:1) and dilute with 2N
-Make it acidic to PH=3 with hydrochloric acid. Next, shake with ether three times and adjust the pH of the ether phase to 4.5 with pyridine.
Shake with water, dry the ether phase and evaporate to dryness. This residue is silicic acid gel (Merck)
200g with chloroform:acetone=8:2(1) as eluent, then _CHCl3 :MeOH
Purify by =6:4 (1.2).

The pure portion is evaporated, triturated with hexane and recrystallized from acetate-petroleum ether. N-Palmitoyl-S- with melting point 62-65℃
[(2,4-ethylidene)-erythrityl]-
Colorless crystals of (R)-cysteine are obtained.

Hydrolysis of this compound was carried out at 80°C with 3% _HBF4 .
It will take 4.5 hours.

8.2 g of ethylidene derivative and 100 g of dimethoxyethane
Treat with 100 ml of 3% HBF ₄ in ml. Then, upon cooling to 60°C, the hydrolysis products precipitate. After suction filtration and drying, it is recrystallized from acetic acid ester. Melting point 160-165℃, sintering from 93℃, Rf=0.285
(CHCl ₃ :MeOH=6:4, thin layer, silicic acid gel (Merck).

Claims (1)

[Claims] 1 The following formula (): [In the formula, R ^a ₁ represents a hydrogen atom or a group R ₁ -CO-, where R ₁ is a C ₁₁ to C ₂₁ -alkyl group, a C ₁₇ -
It is an alkenyl group or a 7-(2-octyl-cyclopropyl)-heptyl group, and R ₂ is C ₁₁ to C ₁₇
- an alkyl group, R ₃ is hydrogen or a palmitoyloxymethyl group, and the asymmetric centers indicated by * and ** indicate the above configuration]. Di-substituted (R)
-Cysteine derivatives and mixtures of epimeric R- and S-compounds at the C ^** atom, and salts thereof. 2. The compound or salt thereof according to claim 1, wherein R ₃ is hydrogen. 3. The compound according to claim 1 or 2, wherein R ^{a 1} _is a group R ₁ -CO- of lauric acid, palmitic acid, stearic acid, behenic acid, oleic acid, or dihydrosterucric acid, Or its salt. 4. The compound according to claim ₁ or 2, or a salt thereof, wherein R ^a 1 is hydrogen. 5 The following formula: (wherein R ₁ CO- is an acyl group of lauric acid, palmitic acid, stearic acid, behenic acid, oleic acid or dihydrosteruclic acid, and
R ₂ CO- is an acyl group of lauric acid, myristic acid, palmitic acid or stearic acid), or an ammonium salt or alkali metal salt thereof, as defined in claim 1. Or alkaline earth metal salts. 6. The compound or salt thereof according to claim 1, which is N-palmitoyl-S-[2(R),3-dilauroyloxypropyl]-(R)-cysteine. 7 The following formula: (wherein, R ₂ —CO— is an acyl group of lauric acid, myristic acid, palmitic acid, or stearic acid) or a salt thereof according to claim 1. 8. The compound or salt thereof according to claim 7, which is N-palmitoyl-S-[2(R),3-dihydroxypropyl]-(R)-cysteine. 9 Claims 6 to 8 which are ammonium salts, alkali metal salts, or alkaline earth metal salts
A salt of a compound according to any one of paragraphs. 10** The compound according to any one of claims 1 to 5, 7, and 9, having the (R)-configuration at the C-atom.