JPH082899B2 - Method for producing perhydro-1,4-thiazepine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel perhydro-1,4-thiazepine derivative which is a synthetic intermediate for an ACE inhibitor (described in European Patent Publication 0161801) useful as an antihypertensive drug. It is about the manufacturing method.

As a method for producing the compound having the general formula (II) described below,
The following methods are specifically disclosed in the above European Patent and Japanese Patent Application No. 60-202164.

In the above formula, R ¹ and R ² represent an amino-protecting group, and R 1
Has the same meaning as described above.

That is, the amino group of the raw material L-cysteine is protected,
After the steps of Michael addition, reduction, dehydration condensation, and deprotection,
The target compound (II) is obtained. In the production method, a relatively expensive protecting reagent is used to protect the amino group with a protecting group such as 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butoxycarbonyl or phthaloyl. However, a complicated step of removing those protecting groups according to a corresponding deprotection method is required. Therefore, as a result of various studies of the reaction in each step, the present inventors conducted the reaction without protecting the amino group, and as a result of the organic synthesis reaction, the di-diamine normally expected in the α-amino acid derivative was predicted. No ketopiperazine type condensation product was obtained, and the target compound (II) was unexpectedly obtained in good yield.
The present invention has been completed and the present invention has been completed.

Structure of the Invention The present invention has a general formula (Wherein R represents a 2-thienyl group or a 3-thienyl group.), The reactive derivative at the carboxy group of the cysteine derivative or an acid addition salt thereof is subjected to a condensation reaction in the presence of a base, if necessary. A general formula characterized by (Wherein R has the same meaning as described above) and relates to a process for producing a perhydro-1,4-thiazepine derivative.

Next, the method of the present invention will be described in detail. The compound having the general formula (I), which is a starting material of the present invention, is a novel compound, and is represented by the following formula: (In the formula, R has the same meaning as described above.) Compound (III) is subjected to a Michael type addition reaction to give compound (IV).
And is obtained by reducing this. As the solvent for the first Michael reaction, water-containing methanol, water-containing ethanol, water-containing isopropanol, water-containing acetone,
Examples thereof include water-containing acetonitrile, water-containing tetrahydrofuran, water-containing dioxane or a mixed solvent of these with dichloromethane, dichloroethane, chloroform and the like. When carrying out the reaction in such a solvent, it is desirable to add a base. Examples of such a base include amines such as triethylamine, N-methylmorpholine, N, N-dicyclohexylamine, pyridine, picoline, lutidine and dimethylbenzylamine, sodium hydrogen carbonate, sodium carbonate,
Examples thereof include carbonates such as potassium hydrogen carbonate and potassium carbonate, and metal hydroxides such as caustic soda and caustic potash. The reaction also proceeds in acetic acid or formamide, in which case no addition of base is required. Reaction temperature is -30 ℃
It is carried out at 100 ° C., and the reaction time is usually 30 minutes to 10 hours. After completion of the reaction, the target compound (IV) of this reaction can be collected from the reaction mixture according to a conventional method. For example, if a base is used, it can be neutralized with acetic acid to obtain the target compound (IV).
Is collected, and the solvent is distilled off from the liquid, and water is added to precipitate crystals. Further, if necessary, it can be purified by recrystallization by dissolving it in a suitable solvent, for example, a solvent such as hydrous acetic acid or methanol acetic acid and concentrating it. The reaction mixture can be extracted with hydrochloric acid and subjected to the next step without isolation and purification of the nitro compound (IV).

Examples of the reduction method of the obtained compound (IV) include catalytic reduction using a metal such as platinum, palladium, Raney-Nitzkel, and rhodium, or a mixture thereof with any carrier, as a catalyst, lithium borohydride, sodium borohydride. , Reduction with a metal hydride such as potassium borohydride, reduction with a metal such as tin, zinc and iron and an acid such as hydrochloric acid, acetic acid, etc., but industrially inexpensive tin and hydrochloric acid or acetic acid. Reduction with water is preferred. The reaction temperature varies depending on the reducing means, but is generally about -20 ° C to 100 ° C. After completion of the reduction reaction, the target compound (I) can be collected by ordinary chemical treatment. For example, in the case of catalytic reduction, the catalyst is removed and the liquid is concentrated. In the case of, after distilling off excess acid, dilute with water and add caustic alkali to make a metal hydroxide or oxide insoluble in water, or add alkali sulfide to form metal sulfide. The target compound (I) is obtained as a dihydrochloride by concentrating the liquid as hydrochloric acid, adding ethanol to the residue, removing the inorganic substance and concentrating. The compound (I) can be obtained as a free form by adding an appropriate base such as triethylamine to the ethanol solution. The compound (I) contains two kinds of optical isomers, but if necessary, a suitable solvent such as hydrous methanol,
Each optically active substance can also be divided by fractional recrystallization with water-containing acetone or the like. Compound (I) is
In addition to the above-mentioned hydrochloride, the following reaction can be carried out as a salt of various mineral acids or organic acids.

Then, the compound (I) is intramolecularly condensed to give perhydro-1,4
The method of the present invention for producing a thiazepine derivative can be carried out in the presence of a base, if necessary, by using the compound (I) as a reactive derivative of a carboxy group or an acid addition salt thereof. Examples of the reactive derivative used include lower alkyl esters such as methyl ester and ethyl ester, acid chlorides, acid halides such as acid bromide; p-nitrophenyl ester, 2,4-dinitrophenyl ester, N -Hydroxysuccinimide ester, N-hydroxyphthalimide ester, N-hydroxy-1,3-
Examples thereof include diazaazulanone ester, active ester such as 1-hydroxybenzotriazole ester, active acid amide with an imino group-containing heterocyclic compound such as imidazole, triazole, tetrazole, and 2-oxazolone. The reactive derivative of can be produced from the carboxylic acid (I) according to a known method.

This condensation reaction can be preferably carried out using a lower alkyl ester as a reactive derivative or an active ester / acid addition salt in the presence of a base, and most preferably an active ester / acid addition salt in the presence of a base. Although it can be carried out using an addition salt, the method will be described in detail below.

Examples of the method using an active ester include acid addition salts of the above-mentioned carboxylic acid compound (I) which is a starting material (for example, mineral acid salts such as hydrochloride, hydrobromide and sulfate, or p-
Organic acid salt such as toluene sulfonate) is soluble in a solvent such as dimethylformamide, dimethylacetamide, formamide, hexamethylphosphoramide, etc. to give N-hydroxysuccinimide, N-hydroxyphthalimide Such an esterification reagent as described above, and then a condensing agent used for peptide peptide synthesis, for example, N,
Addition of N'-dicyclocarbodiimide and the like completes the esterification. The reaction temperature is -40 ° C to 80 ° C, and the reaction time is 5 minutes to 24 hours. The method for collecting the target active ester form from the reaction mixture is such that the precipitated dicyclohexylurea is removed and a liquid insoluble or sparingly soluble solvent for the active ester form, for example, benzene, toluene, ethyl acetate, acetone, cyclohexane, n- Although any one of hexane, diethyl ether, diisopropyl ether, etc. is added for precipitation and collection, a base can be added to carry out the ring-closing reaction without isolating the active ester form. Alternatively, the above-mentioned solvent may be added without removing the urea body and the mixture may be isolated as a mixture of the active ester body and the urea body, and the following ring-closing reaction may be carried out, and then the urea body may be isolated.

The ring closure reaction of the active ester thus obtained is carried out by reacting in a suitable solvent, preferably a halogenated hydrocarbon solvent in the presence of a base. Such bases include pyridine, picoline,
Examples thereof include triethylamine, dimethylbenzylamine, dicyclohexylamine, N-methylmorpholine, the reaction temperature is -50 ° C to 50 ° C, and the reaction time is 1 hour to 10 hours.
Time. The object compound (II) of the present invention can be collected from the reaction mixture by a conventional method such as column chromatography or recrystallization. Further, in the case of containing two kinds of optical isomers, each isomer can be resolved by both fractional crystallization methods.

As a method using a lower alkyl ester, a conventional method for esterifying an amino acid from the carboxylic acid compound (I),
For example, a lower alkyl ester / acid addition salt obtained by reacting in a lower alkanol in the presence of hydrochloric acid gas, sulfuric acid or phosphorus oxychloride is obtained, and this is added to a suitable base (caustic alkali, sodium methoxide, sodium ethoxide, The reaction is completed by turning it into a free form with potassium carbonate, sodium carbonate, etc.) and heating. At this time, when a salt of a base and a weak acid (for example, pyridine; acetic acid, picoline; propionic acid, etc.) is added, the reaction tends to be promoted. The reaction temperature is 30 ° C to 120 ° C, and the reaction time is 1 hour to 10 hours.
The target compound (II) can be collected from the reaction mixture by a conventional method such as column chromatography.

EFFECTS OF THE INVENTION The present invention provides a perhydro-1,4-thiazepine derivative (I
It provides an improved manufacturing method of I).

That is, in the production method of the target compound (II) using L-cysteine as a starting material, the production method of the present invention carried out without protecting the amino group thereof saves reagents and shortens the steps as compared with the conventional methods. In addition, when using the active ester method, the total yield from the starting material L-cysteine to the target compound (II) (total yield)
d) could be improved.

The compound (II) obtained according to the present invention is disclosed in Japanese Patent Application No. 60-2
The method described in the specification of No. 02164 can lead to a pharmaceutical compound useful as an antihypertensive agent exhibiting an ACE inhibitory action.

Next, the present invention will be described in more detail with reference to Examples and Reference Examples.

Example 1. S- [2-amino-1- (2-thienyl) ethyl] L-
Cysteine / N-hydroxysuccinimide ester /
Dihydrochloride S- [2-amino-1- (2-thienyl) ethyl] L
-Cysteine dihydrochloride 1g to dimethylformamide 5ml
Melt, add N-hydroxysuccinimide 360 mg and dicyclohexylcarbodiimide 650 mg, and add at room temperature to 3
Stir for 0 minutes. Precipitated crystals (dicyclohexylurea)
Was removed, washed with a small amount of dimethylformamide, the solution and the washing solution were combined, 100 ml of ethyl acetate was added thereto, and the precipitated crystals were collected and dried to obtain 1.26 g of the objective.

IR spectrum (Nujol mull) cm ^-1 : 2950,1780,1740,1730,1710,1760,1700,1220,1100,1080,
710,660 Example 2.6 6 (R) -Amino-5-oxo-2 (S)-(2-thienyl) perhydro-1,4-thiazepine 1.5 g of S-[(1S) -2-amino-1- (2-thienyl) ethyl] -L-cysteine-dihydrochloride was dissolved in 7.5 ml of dry dimethylformamide and stirred under cooling with water. 650 mg of N-hydroxysuccinimide and 1.12 g of dicyclohexylcarbodiimide are added, and the mixture is stirred at room temperature for 30 minutes. 50 ml of dry ethyl acetate is added and the precipitate is collected and washed with the same solvent.

Then, 45 ml of dry dichloromethane is added and 2.62 ml of triethylamine is added at -30 ° C under stirring. After stirring at -10 ° C for 1 hour, ice cooling for 30 minutes and room temperature for 30 minutes, 10 ml of water is added.
The liquid was separated and the aqueous layer was separated with 10% methanol-dichloromethane 20
Extract twice with ml. The organic layers were combined and concentrated, and the residue was subjected to silica gel column chromatography using 5% methanol-dichloromethane as a solvent system to obtain the desired product. Yield 692 mg Melting point 158 ° C [α] _D 52.7 ° (C = 1.00 DMF) nmr spectrum (DMF-d ₇ ) δ (ppm): 2.55 to 2.85 (m, 2H) 3.4 to 4.45 (m, 4H) 6.95 to 7.20 (M, 2H) 7.50 to 7.65 (m, 1H) 7.80 (brt, 1H, J = 7Hz) Example 3. S- [2-amino-1- (2-thienyl) ethyl] -L
-Cysteine / N-hydroxyphthalimide ester /
Dihydrochloride S- [2-amino-1- (2-thienyl) ethyl] L
-Cysteine dihydrochloride 3.0 g in dimethylformamide 15
Dissolve in 1.5 ml, add N-hydroxyphthalimide (1.53 g) and dicyclohexylcarbodiimide (1.94 g), and mix at room temperature for 3 minutes.
Stir for 0 minutes. The precipitated dicyclohexylurea was removed, washed with dimethylformamide, combined with the solution, and ethyl acetate was added to this to precipitate the desired product, which was collected and dried.

Yield 4.1 g IR spectrum (Nujol mull) cm ^-1 : 2900,1820,1790,1750,1730,1650,1470,1380,700 Example 4.6 (R) -Amino-5-oxo-2 (S)- (2-thienyl) perhydro-1,4-thiazepine To 3.0 g of the ester dihydrochloride obtained in Example 3, 60 ml of dichloromethane is added, and 3.6 ml of triethylamine is added dropwise while cooling and stirring at -30 ° C. Then 30 at -20 to -10 ℃
Min, stirred at 0 ° C for 30 minutes, at room temperature for 30 minutes, washed with 5% aqueous sodium hydrogen carbonate and water, extracted the aqueous layer once with 5% methanol and dichloromethane, combined with the dichloromethane layer, and evaporated the solvent under reduced pressure. The product was subjected to silica gel column chromatography, eluted with 5% methanol and dichloromethane, distilled off the solvent, dissolved in a small amount of 5% methanol and dichloromethane, and concentrated under reduced pressure with ethyl acetate to precipitate crystals. , 0.43 g of the desired product was obtained. This is consistent with the crystals obtained in Example 2.

Example 5. S- [2-amino-1- (2-thienyl) ethyl] -L
-Cysteine methyl ester S- [2-amino-1- (2-thienyl) ethyl]-
Add 160 ml of methanol to 16 g of L-cysteine dihydrate and add hydrochloric acid gas while stirring. When the contents are completely dissolved, the solution is refluxed, and the reflux is continued while passing hydrochloric acid gas for 5 hours. Then, the solvent is distilled off, and white crystals remain. When ethyl acetate is added to this and collected, 18.3 g of the desired dihydrochloride is obtained. To this crystal are added 200 ml of methanol and 21 ml of 28% sodium methoxide-methanol solution, and the mixture is stirred in an ice-water bath for 15 minutes. Then, the solvent was distilled off under reduced pressure, ethanol was added to the residue, the insoluble matter was removed, and the liquid was concentrated under reduced pressure to obtain 14.3 g of a candy-like target product.

nmr spectrum (CDCl ₃ ) δ (ppm): 1.58 (brs, 4H) 2.66 to 2.90 (m, 2H) 3.09 (d, 2H, J = 7Hz) 3.47 to 3.66 (m, 1H) 3.72 (s, 3H) 4.19 (T, 1H, J = 7Hz) 6.82 to 7.06 (m, 2H) 7.18 to 7.35 (m, 1H) Example 6.6 (R) -amino-5-oxo-2 (S)-(2-thienyl) Perhydro-1,4-thiazepine 2.1 g of the methyl ester compound obtained in Example 5 was added to pyridine
Add 1 ml and acetic acid 0.5 ml and stir at 58-60 ° C for 1 hour. Then, the mixture was cooled, dissolved in 10% methanol and dichloromethane, subjected to silica gel chromatography, eluted with 10% methanol and dichloromethane, and the target product was treated in the same manner as in Example 4 to obtain the target product.

Example 7. 6 (R) -Amino-5-oxo-2 (S)-(3-thienyl) perhydro-1,4-thiazepine S- [2-amino-1- (3-thienyl) ethyl-L
-Cysteine dihydrochloride 8g to dimethylformamide 40ml
Slightly heat and melt, N-hydroxysuccinimide
Add 3.02 g and 5.42 g of dicyclohexylcarbodiimide and stir at room temperature for 40 minutes. Add 150 ml of dry ethyl acetate,
The precipitates are collected, washed with ethyl acetate, 120 ml of dry dichloromethane is added to the crystals, cooled to -25 to -30 ° C, and 14 ml of triethylamine is added dropwise with stirring. Then -20
Stirring was continued for 1 hour at ℃, 30 minutes at -10 to 0 ℃, 30 minutes at room temperature, 80 ml of water was added to remove insoluble matter (dicyclohexylurea), the solution was separated, and the aqueous layer was mixed with 5% methanol / dichloromethane. Extract with, combine with the dichloromethane layer and evaporate the solvent under reduced pressure. The residue was dissolved in 5% methanol / dichloromethane and chromatographed on silica gel.
Elute with dichloromethane, collect the fraction of the target substance, evaporate the solvent, dissolve in 5% methanol / dichloromethane, add ethyl acetate and concentrate. The target substance precipitates first, so collect this, wash with ethyl acetate, Dried.

Yield 1.3 g [α] _D + 57 ° (C = 1.0 DMF) nmr spectrum (DMF-d ₇ ) δ (ppm): 2.5 to 3.1 (m, 2H) 3.46 to 4.95 (m, 2H) 4.02 to 4.23 (m, 2H) 7.1 to 7.28 (m, 1H) 7.43 to 7.6 (m, 2H) 7.72 (brt, J = 7Hz) Reference Example 1. S- [2-nitro-1- (2-thienyl) ethyl] -L
-Cysteine L-Cysteine 5.0 g was suspended in dichloromethane 100 ml, and the mixture was stirred in ice water under cooling at 3 to 5 ° C to give 1-nitro-2.
6.5 g of-(2-thienyl) ethylene, triethylamine 5.
Add 7 ml, 3 ml of water and 20 ml of ethanol and continue stirring for 1.5 hours. Then add 2.5 ml of acetic acid and stir for 10 minutes. The precipitated jelly-like solid is collected and washed with ethyl acetate and then ethanol. When the solution and the washing solution are combined and concentrated, a further small amount of crystals are precipitated. Therefore, if the same crystals are collected, combined with the preceding crystals and dried, 10.4 g of the desired product is obtained. Dissolve this in acetic acid water (acetic acid: water = 1: 2), add activated charcoal, and pass.
Crystals were precipitated upon concentration, so a high purity product was obtained by collecting, washing with ethanol and drying.

mp 214 ° C (blackening) nmr spectrum (CD ₃ CO ₂ D + D ₂ O) δ (ppm): 3.02 to 3.3 (m, 2H) 4.0 to 4.3 (m, 1H) 4.7 to 5.1 (m, 3H) 6.85 to 7.2 (M, 2H) 7.3 to 7.5 (m, 1H) Reference Example 2. S- [2-nitro-1- (3-thienyl) ethyl] -L
Cysteine When 6.5 g of 1-nitro-2 (3-thienyl) ethylene was used instead of 6.5 g of 1-nitro-2- (2-thienyl) ethylene of Reference Example 1, the same reaction and treatment was carried out to obtain 10.6 g of the target compound. Was given.

mp 165 ° C (blackening) nmr spectrum (CD ₃ COOD + D ₂ O): 3.0 to 3.3 (m, 2H) 4.02 to 4.20 (m, 1H) 4.8 to 5.05 (m, 3H) 7.12 to 7.2 (m, 1H) 7.4 ~ 7.55 (m, 2H) Reference Example 3. S- [2-amino-1- (2-thienyl) ethyl] -L
-Cysteine dihydrate S- [2-nitro-1- (2-thienyl) ethyl]-
L-Cysteine 10g in water 100ml and concentrated hydrochloric acid 200ml, acetic acid 3
0 ml was added, and 30 g of tin powder was added little by little while stirring in an ice-water bath. Then 1 hour at room temperature, 5 hours at 35-45 ° C, then 55
When heated and stirred at 1 ° C. for 1 hour, the tin is completely dissolved to form an almost colorless solution. Concentrate under reduced pressure and add water to the remaining syrap.
When 0 ml was added and melted, a 20% aqueous sodium hydroxide solution was added to adjust the pH of the solution to 6.0, and the mixture was heated at 65 to 70 ° C for 30 minutes, and the precipitated white crystals became dark brown. Pass the heat and wash the insoluble matter with hot water. When the liquid is cooled, it becomes cloudy, so repeat. Adjust the pH of the solution to 1.0 with hydrochloric acid and concentrate under reduced pressure. To the residue was added 150 ml of ethanol to remove insoluble matter, washed with ethanol, and triethylamine was added to the solution little by little until white crystals did not precipitate. After cooling in an ice-water bath for 30 minutes, collect,
Wash with ethanol.

Water (80 ml) is added to the crude crystals, activated carbon is added, and the mixture is stirred. Crystals are precipitated when the liquid is concentrated under reduced pressure. When ethanol was added and collected and dried, 9.2 g of the desired product was obtained.

Melting point 242 to 245 ° C (decomposition) [α] _D + 38 ° (C = 1.00 H ₂ O) Analytical value C ₉ H ₁₄ N ₂ S ₂ O ₂ · 2H ₂ O Calculated value C, 38.28; H, 6.43; N , 9.92; S, 22.67 Experimental value C, 38.03; H, 6.36; N, 9.96; S, 22.71 nmr spectrum (D ₂ O) δ (ppm): 3.00 to 3.20 (m, 2H) 3.60 to 3.80 (m, 2H ) 3.73 to 3.98 (m, 1H) 4.50 to 4.75 (m, 1H) 7.0 to 7.35 (m, 2H) 7.5 to 7.68 (m, 1H) Reference Example 4. S- [2-amino-1- (2-thienyl) ) Ethyl] -L
-Cysteine dihydrochloride S- [2-amino-1-obtained by the method of Reference Example 3
(2-Thienyl)]-L-cysteine dihydrate (10 g) was added with 30 ml of water and 7.4 ml of conc. It was crystallized by adding 100 ml of ethyl acetate and a small amount of seed crystals to this, which was collected, washed with ethyl acetate and dried. Yield 11.3 g nmr spectrum (D ₂ O) δ (ppm): 3.0 to 3.3 (m, 2H) 3.40 to 3.71 (m, 2H) 4.0 to 4.32 (m, 1H) 6.96 to 7.35 (m, 2H) 7.45 to 7.68 (M, 1H) Reference Example 5. S-[(1S) -2-Amino-1- (2-thienyl) ethyl] -L-cysteine dihydrate S- [2-amino-1-obtained by the method of Reference Example 3
(2-thienyl) ethyl] -L-cysteine dihydrate
Dissolve 10 g in 50 ml of water, add 60 ml of methanol, and leave at room temperature to precipitate crystals. The desired compound was obtained by collecting the crystals and repeating the same procedure for the crystals.

[Α] _D −87 ° (C = 1.00 H ₂ O) nmr spectrum (D ₂ O) δ (ppm): 3.06 (d, 2H, J = 7Hz) 3.55 (d, 2H, J = 7Hz) 3.84 (t , 1H, J = 7Hz) 4.65 (t, 1H, J = 7Hz) 6.95 to 7.30 (m, 2H) 7.45 to 7.65 (m, 1H) Reference Example 6. S- [1S) -2-amino-1- ( 2-thienyl) -ethyl] -L-cysteine dihydrochloride S-[(1S) -2-amino-1- (2-thienyl) -ethyl] -L-cysteine obtained by the method of Reference Example 5
When 10 ml of water and 1.5 ml of concentrated hydrochloric acid were added to 2.5 g of the dihydrate and melted, and treated in the same manner as in Reference Example 4, the target compound 2.
8 g was obtained.

[Α] _D −87 ° (C = 1.00 H ₂ O Analytical value C ₉ H ₁₆ Cl ₂ N ₂ O ₂ S ₂ Calculated value C, 33.85; H, 5.05; N, 8.81; S, 20.09; Cl, 22.21 Experimental value C, 33.79; H, 5.16; N, 8.71; S, 20.17; Cl, 22.32 nmr spectrum (D ₂ O) δ (ppm): 3.56 to 3.68 ((m, 2H) 4.08 (d, 2H, J = 7Hz) 4.58,4.65 (dd, 1H, J = 7Hz) 5.25 (t, 1H, J = 7Hz) 7.52 to 7.86 (m, 2H) 8.0 to 8.18 (m, 1H) Reference Example 7. S- [2-amino -1- (3-thienyl) ethyl-L-
Cysteine dihydrate S- [2-nitro-1- (3-thienyl) ethyl]-
When 10 g of L-cysteine was reacted and treated in the same manner as in Reference Example 3, 9.2 g of the desired product was obtained.

Melting point 242 ° C (decomposition) ▲ [α] ²⁴ _D ▼ + 25 ° (C = 1.006 H ₂ O) Analytical value Calculated value as C ₉ H ₁₈ N ₂ S ₂ O ₄ C, 38.28; H, 6.43; N, 9.92; S, 22.67 Experimental value C, 38.12; H, 6.32; N, 9.80; S, 22.55 nmr spectrum (D ₂ O) δ (ppm): 3.41 ~ 3.62 (m, 2H) 3.89 ~ 4.10 (m, 2H) 4.15 ~ 4.33 (m, 1H) 4.82 to 5.05 (m, 1H) 7.69 to 7.80 (m, 2H) 7.98 to 8.20 (m, 1H) Reference Example 8. S- [2-amino-1- (3-thienyl) ethyl- L
-Cysteine dihydrochloride S- [2-amino-1- (3-thienyl) ethyl-L
-Cysteine dihydrate 5.0g to water 15ml and concentrated hydrochloric acid 3.7m
When l was added and melted and treated in the same manner as in Reference Example 4, 5.6 g of the target product was obtained.

nmr spectrum (D ₂ O) δ (ppm): 3.5 to 3.74 (m, 2H) 3.95 to 4.15 (m, 2H) 4.4 to 4.6 (m, 1H) 4.82 to 5.05 (m, 1H) 7.7 to 7.88 (m, 1H) 7.9 ~ 8.20 (m, 2H)

Claims (2)

[Claims] 1. A general formula (In the formula, R represents a 2-thienyl group or a 3-thienyl group.) A reactive derivative of the carboxy group of the cysteine derivative having the above or an acid addition salt thereof is subjected to a condensation reaction in the presence of a base, if necessary. A general formula characterized by (In the formula, R has the same meaning as described above.) A method for producing a perhydro-1,4-thiazepine derivative having 2. An active ester of cysteine derivative (I).
The perhydro-1,4-as claimed in claim 1, characterized in that the acid addition salt is subjected to a condensation reaction in the presence of a base.
Process for producing thiazepine derivative (II).