JPS62212379A - Tetrahydrothiazepine derivative - Google Patents

Abstract

NEW MATERIAL:A tetrahydrothiazepine derivative expressed by formula I (R<1> is alkyl, cycloalkylalkyl or aralkyl; R<2> and R<4> are carboxy-pretecting group R<3> is aryl or heterocyclic group; A is lower alkylene). EXAMPLE:tert-Butyl alpha-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-5- oxo-4,-5,6,7-tetrahydro-2-(2-thienyl)-1,4-thiazepin-4-yl)}acetate. USE:With inhibitory activity against angiotensin converting enzymes and useful as a remedy for hypertension. PREPARATION:For example, as shown in the reaction formula, a compound expressed by formula II is reacted with a compound expressed by formula III in the presence of a base and preferably a phase-transfer catalyst, e.g. tetra- n-butylammonium bromide, etc., in a solvent, e.g. hexane, etc., to afford the aimed compound expressed by formula I.

Description

[Detailed Description of the Invention] Seven Ws? This invention relates to tetrahydrothiazepine derivatives that can be used as synthetic intermediates.

The present inventors conducted synthetic research for the purpose of research and development of antihypertensive agents, and found that a new compound having the general formula CD described below has inhibitory activity against angiotensin converting enzyme and is useful as a therapeutic agent for cylindrical hypertension. They discovered this and completed the present invention.

The present invention relates to the general formula (wherein R1 represents an alkyl A/group, a cycloalkylalkyl group, or an aralkyl group, and R2 and R4 are the same or different and represent a hydrogen atom or a carboxy group!!
group, R3 represents an aryl group or a moat group, A
represents a lower alkylene group. This invention relates to a novel tetrahydrothiazepine derivative represented by

The compound represented by the above general formula CI) contains an un★ carbon atom at the position rIL (in some cases other positions) represented by an asterisk, so it is an optically pure diastereoisomer or diastereoisomer. Racemic stereoisomers or mixtures of diastereoisomers may be present. The present invention can encompass any of these stereoisomeric forms.

Next K, in the general formula [I], [e exchange &R', R2,
R'S.

R4 and people will be specifically explained.

The alkyl group in R1 is an alkyl group having 1 to 9 carbon atoms, such as methyl.

Examples of cycloalkylalkyl groups include ethyl, n-propyl, isopropyl, n-butyl, inbutyl, tert-butyl, pentyl, neopentyl, hexyl, octyl, and nonyl.

A cycloalkyl group having 5 to 7 carbon atoms has 1 carbon number
An alkyl group having a total of two atom groups, such as cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylethyl, 2-cyclohexylethyl, cycloheptylmethyl, 2-cycloheptylethyl, etc.; examples of aralkyl groups include benzyl, phenethyl, etc. , 1-naphthylmethyl, 1-naphthylethyl, 2-naphthylmethyl,
Examples include 2-naphthylethyl and 2-indanyl.

These cycloalkyl groups or aralkyl groups may have a substituent, and such substituents include those with a carbon number of 1
to 4 lower alkyl groups (e.g. methyl, ethyl, n
-Furovil, isopropyl, n-butyl, imbutyl, tert-butyl, etc.), lower alkoxy groups having 1 to 4 carbon atoms (for example, methoxy, fluorine, chlorine,
bromine, etc.), carbon I! 1 to 4 lower alkylthio groups (
Examples include methylthio, ethylthio, etc.), and 1 to 3 of these may be used the same or in combination.

As the carboxylic acid preservative group in R2 and R4,
It refers to an ester residue that is widely known as a protective group in organic synthetic chemistry or that can be pharmacologically converted into a carboxyl group in vivo.Such a protective group is a carbon Number 1 to 6 alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, inbutyl, tert-butyl, n-pentyl, n-hexyl, etc.), aralkyl groups (e.g. benzyl, diphenylmethyl, etc.) , 1-indanyl, 2-indanyl, 1- (1,2, 4-'y''trahydronaphthyl)
, 2-(1,L 3.4-tetrahydronaphthyl),
phthalidyl, etc.), aryl groups (eg, phenyl, etc.), and silyl groups (eg, trimethylsilyl, tert-butyldimethylsilyl, etc.). The above-mentioned carrier groups include alkyl, halogen, hydroxy, alkoxy, acyloxy, oxy, carboxy, alkoxycarbonyl, alkoxycarbonyloxy, acylamino, nitro, cyano, amino, monoalkylamino, dialkylamino,
Substituents such as alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, 2-oxo-1,3-dioxolen-4-yl groups, etc. may be present, and these substituents may be the same or in combination, and may have 1 to 3 substituents. It's sandwiched and the temperature is also good. Examples of such substituents include 2,2,2-trichloroethyl%2-iodoethyl, etc. for halogen, 2-hydroxyethyl, 2,3-dihydroxypropyl, etc. for droxy, and methoxymethyl for alkoxy. , 2-methoxyethoxymethyl, p-methoxybenzyl, etc., acyloxy such as acetoxymethyl, 1-acetoxymethyl, pivaloyloxymethyl, etc., oxy such as phenacyl, alkoxycarbonyl such as methoxycarbonylmethylgin, alkoxycarbonyloxy For nitro, p-nitrobenzyl, etc. are ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, etc.
For cyan, cyanethyl, etc. For alkylthio, methylthiomethyl, ethylthiomethyl, etc. For arylthio, phenylthiomethyl, etc. For alkylsulfonyl, 2-(methanesulfonyl)ethyl, etc. For arylsulfonyl, 2-(benzenesulfonyl) Ethyl, etc., 2-oxo-1゜3-dioxolene-4-
In yl, (5-methyl-2-oxo-1,3-
dioxolen-4-yl)methyl, (5-phenyl-2
-oxo-1,3-dioxolene-4-i/I/)methyl, and the like. What are the retention groups of these carboxylic acids?

It is the object of the present invention not to modify the spirit of this invention as much as possible (extensive variations are possible).

As the aryl group of R5, phenyl, 1-naphthyl,
Examples of the heterocyclic group include 5- or 6-hydrogen bases containing 1 to 3 atom atoms, oxygen atoms, or sulfur atoms, such as furyl, chenyl, imidazolyl, thiazolyl, oxasilyl, Examples include inoxasilyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like.

These aryl groups or heterocyclic groups may have a substituent, and such substituents include lower alkyl groups having 1 to 4 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, te
rt-butyl, etc.), and aryl groups (eg, phenyl, naphthyl, etc.).

The lower alkylene group of A is an alkylene group having 1 to 2 carbon atoms, such as methylene, ethylene, ethylidene, and the like.

Suitable compounds in the general formula [1] include Bl
is n-butyl, inbutyl, n-pentyl, inpentyl, neopentyl, n-hexyl, inoctyl, n-
M-button-shaped or split-chain alkyl groups having 4 to 9 carbon atoms such as octyl and n-nonyl; 5-membered or 6-μ cycloalkylethyl groups such as 2-cyclopentylethyl and 2-cyclohexylethyl; Benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 1
- An aralkyl group having T to 12 carbon atoms, such as naphthylethyl, 2-naphthylethyl, and 2-indolyl.

R2 is a hydrogen atom, or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-
Straight chain or branched chain alkyl groups having 1 to 6 carbon atoms such as pentyl, n- to Φyl, aralkyl groups such as benzyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, 1- (Ethoxycarbonyloxy)ethyl, (5-methyl-2-oxo-1゜3-dioxolen-4-yl)methyl, which can be easily attached to a carboxy group in vivo, and R3 or Phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-chenyl, 3-chenyl, 3-
Methylthiophene-2-yl, 5-methylthiophene-
2-yl, 4-thiazolyl, 2-methylthiazo-/I/
-4-yl, 2-phenylthiazol-4-yl12-
Pyridyl, 3-pyridyl, 4-pyridyl, pyrazine-2
aryl or multicyclic group such as -yl, where R4 is a methylene group, and R4 is a hydrogen atom, tert-butyl, methoxymethyl, 2.2.2-tri/lolethyl, allyl, benzyl, p-nitrobenzyl , p-methoxybenzyl, diphenylmethyl, or acetoxymethyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, phthalidyl, (5-methyl-2 -oxo-1,3-
Examples include compounds that are stomach-retaining groups that can be easily converted into carboxy groups in vivo, such as dioxolen-4-yl)methyl.

The novel compound CI) of the present invention can be converted into a pharmaceutically acceptable salt by treatment with an acid or base according to a conventional method. Examples of such polyaddition salts include non-acidic acids, such as hydrohalic acids (e.g.
hydrobromic acid, etc.), salts of sulfuric acid, phosphoric acid, nitric acid, etc.;
Addition salts such as pyrochloric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, etc.) are available. In addition, as salts with bases, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., calcium hydroxide, magnesium hydroxide, etc.)
, ammonium hydroxide, aluminum hydroxide, organic salts (eg, triethylamine, dicyclohexylamine, cinchonine, guanidine, quinine, etc.), salts with basic amino acids (eg, lysine, alkynine, etc.), and the like.

As specific compounds represented by the general formula [I] of the present invention, the compounds described below are exemplified (in the formula, R',
R2, 15, R4 and A have the same meanings as described above, and X represents a halogen atom or a sulfonyloxy group. ) In the general formula [■], examples of the halogen atom of substituted or unsubstituted lower alkanesulfonyloxy groups and pencenesulfonyloxy, p-
Examples include substituted or unsubstituted aromatic sulfonyloxy groups such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, and m-nitrobenzenesulfonyloxy.

The reaction between compound [■] and compound [melon] is carried out in the presence of a base in a suitable solvent that does not support this reaction. Examples of solvents include hydrocarbons such as hexane and benzene, halogenated hydrocarbons such as dichloromethane and 1゜2-dichloroethane, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, and acetone. Examples include ketones, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, and dimethylsulfoxide. There are no particular limitations on the base used, but alkali or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, Mf
l.

Alkali metal bicarbonates such as potassium bicarbonate, metal fluorides such as potassium fluoride, cesium fluoride, alkali metal hydrides such as sodium hydride, lithium hydride, triethylamine, pyridine, picoline, tetraethylammonium hydroxide. There are four organic groups such as In addition, this reaction can be carried out in a two-layer system of water and a water-insoluble solvent such as dichloromethane, chloroform, etc., using a phase-j transfer catalyst such as tetra-n-butylammonium bromide, penzyltriethylammonium iodide, etc. When doing this, an alkali metal hydroxide such as hydric soda or hydric potash can also be used. Reaction temperature is usually 0-120℃
The reaction time varies depending on the type of solvent and base used, but is usually 1 hour to 3 days.

After completion of the reaction, the target compound of this reaction can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent such as ethyl acetate to the reaction mixture, washing the organic mortar with water, drying, and then distilling off the solvent. If necessary, recrystallization, column chromatography, etc. It can be refined with

Reductive conditions for the reaction between compound [...] and compound [N) include, for example, catalytic reduction using a metal such as platinum, veradium, Raney nickel, rhodium, or a mixture thereof with an arbitrary carrier as a catalyst, such as hydrogen. Lithium aluminum oxide, lithium boron hydride, sodium cyanoboron hydride, silicon hydride) IJium, reduction with metal hydrides such as potassium borohydride, metal magnesium) IJium, metal magnesium, etc. and methanol, ethanol, etc. Examples of reaction conditions include reduction with alcohols, and reduction with metals such as iron and zinc and acids such as hydrochloric acid and acetic acid. The above reaction is usually carried out in the presence of water or an organic solvent (for example, methanol, ethanol, tetrahydrofuran, diethyl ether, dioxane, dichloromethane, chloroform, ethyl acetate, benzene, toluene, dimethylformamide, dimethylacetamide, acetic acid, etc.), and the reaction temperature is varies depending on the reducing means, but is generally preferably about -20 to 100°C.

Although the purpose of this reaction can be achieved under normal pressure, the reaction may be carried out under increased pressure or reduced pressure depending on the case.

Among the compounds CD produced in this way, monoester monocarboxylic acid compounds in which R2 is an ester residue and R4 is an aqueous atom or salt, and B2. Dicarboxylic acids in which both R4's are carboxylic atoms or salts are important compounds in medicine. The above monoester monocarboxylic acid compound can be produced by selective removal of the ester residue R4 of a diester compound represented by the formula CI] in which R2 and R4 are both ester residues or groups, or by general It can be produced by a reductive condensation reaction between an amino acid compound in which 84 is a hydrogen atom in the formula CIl''l and a ketoester cy] (12&m ester residue).

In addition, the dicarboxylic acid compound in which both 82 and R4 are hydrogen atoms can be obtained by hydrolyzing the diester compound or monoester compound [I] obtained by the above reaction using an acid or base, or by reducing the ester group. It can also be produced by a target removal method. The reaction conditions are the same as those for the deprotection of the carboxylic acid retaining group R7 in the compound [■] described below.

The raw material compound represented by the general formula [11], that is, the compound represented by the general formula (wherein R3, RA and A have the same meanings as described above), can be produced, for example, by the reaction formula shown below.

(In the formula 13. R4 and A have the same meanings as described above, and R5 and R6 represent a hydrogen atom or a protecting group for an amino group.) In the above formula, a protecting group for an amino group represented by R5 and R6 is a protecting group that is generally well known in general synthetic chemistry, such as 2,2.2-)lychloroethoxycarbonyl, 2-iodoethoxycarbonyl, 2-)luponyl, trimethylsilylethoxycarbonyl, 2-
(p-toluenesulfonyl)ethoxycarbonyl,
Alkoxycarbonyl groups such as tert-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitropenzyloxycarbonyl, etc., acyl groups such as formyl, acetyl, benzoyl, chloroacetyl, trifluoroacetyl, etc. , N-phthaloyl, cyclic diacyl groups such as N-2,3-diphenylmaleinyl, lkm methyl groups such as methoxymethyl, benzyloxymethyl, benzyl, 3,4-dimethoxybenzyl, trityl, isopropylidene, benzylidene, salicylidene alkylidene or aralkylidene groups such as, noacylvinyl groups such as 1-methyl-2-acetylvinyl, 1-methyl-2-benzoylvinyl, and trimethylsilyl.

Examples include silyl groups such as tert-butyldimethylsilyl, but these protecting groups for amino groups are not intended to be limiting.

The starting compound [v] of this reaction formula is a compound described in the patent specifications (Japanese Patent Laid-Open No. 60-215678 and Japanese Patent Application No. 60-291445) already filed by the inventors of the present application. be.

Compound C by oxidation of compound [V] with a halogenating agent
The reaction M) is carried out in an appropriate solvent that does not inhibit this reaction, at a reaction temperature of -80'C to 100'C, for a reaction time of 30 minutes to 240°C.
done in time. The halogenating agent used in this reaction is hypochlorine C#! Examples of solvents include 1-butyl, N-chlorosuccinimide, and N-bromsuccinimide; solvents include hydrocarbons such as n-hexane, cyclohexane, benzene, and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; and tetrahydrofuran. , ethers such as dioxane, ethyl vinegar, esters such as 1'1dn-butyl vinegar, and amides such as dimethylformamide and dimethylacetamide. In this reaction, the yield of compound [■] may be improved by carrying out the reaction in the presence of a base such as pyridine, N-methylmorpholine, triethylamine, Wataru, sodium carbonate, etc. After completion of the reaction, the target compound of this reaction can be collected from the reaction mixture according to a conventional method. For example, the sulfoxide compound can be obtained by adding an organic solvent such as ethyl acetate or dichloromethane to the reaction mixture, washing the organic solvent layer with water, drying, and evaporating the solvent. [■ It can also be produced by heating with l'km anhydride.

Oxidation of compound [v] to compound [■] is a well-known method in organic synthetic chemistry, in which a peracid such as perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, etc. , cyclohexane, benzene, dichloromethane, chloroform, tetrahydrofuran, dioxane, acetic acid, or the like. The reaction temperature is -30°C to 30°C, and the reaction time is 1 hour to 24 hours. After the reaction is completed, the sulfoxide [■] can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent such as ethyl acetate or dichloromethane to the reaction mixture, washing the organic solvent layer with deuterium chloride water, drying, and distilling off the solvent. If necessary, it can be obtained by recrystallization and column chromatography. Can be made from treetops. Compound CI from compound [■]
The conversion to II by heating with an acid anhydride is essentially the same as the reaction known as the Bumeller rearrangement, and the typical acid anhydride used is acetic anhydride. This reaction can use acetic anhydride as a solvent, but toluene,
Solvents such as dioxane, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, etc. may be used. The reaction temperature is 80°C to 150°C, and the reaction time is 1 hour to 24 hours. It has already been mentioned that the target compound ([1] can be collected from the reaction mixture by conventional methods.

B5 of compound [■]. Deprotection of the protective group of the amino group represented by B6 is a well-known method in organic synthetic chemistry. (e.g., R5 is
t-butoxycarbonyl, p-methoxybenzyloxycarbonyl, trityl.

tert-butyldimethylsilyl, etc.), deprotection with zinc dust-acid (for example, R5 is 2.2.2-) lychloroethoxycarbonyl, 2-iodoethoxycarbonyl, etc.)
, tetrakis(triphenylphosphine)palladium (
O)'ftPB1 medium deprotection (e.g., R5 is allyloxycarbonyl, etc.), deprotection by catalytic reduction (e.g., R5 is benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.), hydrazine, methylhydrazine, etc. Examples include parent strain i (for example, R2R6 or phthaloyl).

The solvents used in parent stock reactions vary depending on the deprotection method, but include water, acetic acid, formic acid, etc., alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, and anisole, ketones such as acetone, and dichloromethane. , halogenated hydrocarbons such as chloroform, and hydrocarbons such as benzene and toluene. The reaction temperature and reaction time vary depending on the deprotection method, but are generally from -10°C to 100°C for 30 minutes to -100°C.

It has already been mentioned that the compound represented by the general formula [I] produced in this way has a small angle carbon atom in the molecule, so it exists in the first few optical isomers. These isomers can also be prepared separately. That is, by carrying out the above reaction using 10,000 optical isomers of each of the raw material compounds that have been optically resolved in advance, the corresponding optical isomers of compound CI) can be obtained. If at least 10,000 of the raw material compounds are racemic,
Compound [I] is usually obtained as a mixture of true isomers, but this isomer mixture can be separated, if desired, by a conventional separation method, such as an optically active base (for example, cinchonine, cinchonidine, quinine, quinidine, etc.), an optically active organic acid, etc. (for example, !-camphorsulfonic acid, d-camphorsulfonic acid, etc.), various chromatography methods,
Each isomer can also be separated by treatment using fractional recrystallization or the like.

Effects of the Invention Compound CI of the present invention has the effect of reducing the activity of the enzyme (hereinafter abbreviated as ACE) that converts angiothe/synl to angiotensin l.

Angiotensin ■ is a blood pressure stimulant active substance.

Fart is a substance that causes daytime blood pressure in mammals including humans. In addition to being involved in the production of angiotensin, ACK is also involved in the metabolism of bradykinin, a blood factor substance, and has the effect of converting bradykinin into an inactive form.

The biological activity of the compound [l] of the present invention is planned in vitro (i.
C Biochemica Cushman et al.
l Pharmaco-10gys Volume 20, 1
637 (1971)], ACE and hybril histidyl leucine as a substrate were added to the pH solution containing sodium chloride.
After making an ayaga borate solution of 8,3 and enzymatically reacting at 37"C for 130 minutes, the reaction was stopped with IN hydrochloric acid, the produced hippuric acid was extracted with ethyl acetate, and then the ethyl acetate was distilled off and JAw Dissolve hippuric acid in water, 22
Hippuric acid content is determined from the UV absorption rate at 8 mμ.

By displaying this graph as a white piece against the degree of compound [l], and reading from the graph the half of hippuric acid produced when compound CI) is not included, and the once of CI) of the compound when it is produced, I Cso was determined. The IC5o thus determined is shown in Table 1.

Table 1 Example 3 Compound 3. I X 1G-9 Therefore AC
The compound [I] of the present invention and its pharmacologically acceptable salts which inhibit E activity are useful as agents for diagnosis, prevention or treatment of hypertension. When compound [I] and its pharmacologically acceptable class 1 are used as the above-mentioned medicament, they can be prepared by themselves or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc., and prepared as powders, It can be administered orally or parenterally in the form of pharmaceutical compositions such as granules, tablets, capsules, and ejectables.

The dosage varies depending on the condition of the patient and the administration method, but for example, when administered to an adult patient for the purpose of treating hypertension,
For oral administration, one dose is usually 0.5 to toooq, particularly about 1 to 100η, and for intravenous administration, one dose is about 0.5
~100η, especially about 0.5~10μ is preferable, and it is desirable to administer these medicinal violets once to three times a day depending on the symptoms.

EXAMPLES The present invention will be explained in more detail with reference to Examples and Reference Examples below, but the scope of the present invention is not limited thereto.

Example 1゜2 Ethyl (R)-hydroxy-4-phenyl hexate 0
．． While cooling in a water bath to dissolve 50 g of anhydrous methylene chloride, a mixture of 0.191 pyridine and 47 ml of trifluoromethanesulfonic anhydride Q was added for 40 minutes. 3.8 wings l
was added and the precipitate was removed. 1 solution was evaporated, and the residue was subjected to short silica gel column chromatography using a 1:10 ethyl acetate-cyclohexane solvent system to obtain 075 g of ethyl 4-phenyl-2(R)-trifluoromethanesulfonyloxyacetate as a syrup. This is α−
[8(R)-amino-5-oxo-4,5,6,7-titrahydro-2-(2-chenyl)-1,4-thiazepin-4-yl]acetic acid tert-butyl ester 0.6
5y and triethylamine 0.30-methylene chloride was added to a 5-proof solution of methylene chloride, and after evaporation for 16 hours at room temperature, the residue was subjected to fit H on a silica gel column chromatography using ethyl acetate-cyclohexane 1:4 to obtain a gum-like product. The target compound is 1.01F.

[α] 25-296.8° (cl, DMF).

NMR (CDCj3) δ (ppm): 1.20 (3
H, t, C02CH2C1i3).

1.47 (9H, s, tert-Bu).

1.8-2.2 (2H, m, PhCH2CH2).

2.3-3.0 (3H, m, PhCH2CH2
,NH).

3.0-4.52 C8H,C-14(Co2(4,C
H5)-N.

N-CH2-Co, thiazepine ring 6 and T-position proton].

688 (I H# S-thiazepine ring 3-position proton).

6.8-7.4 (3H, m, thiophene ring proton).

7.21 (SR, s, phenyl group proton).

Actual addition example 2 α-(6(R)-[1(S)-ethoxycarbonyl-3
-phenylpropylamino]-S=oxo-4,5,8
,7-titrahydro-2-(2-chenyl')-1,4
Q ml of trifluoroacetic acid was added to a solution of 1.0 g of tert-butyl ester (f-azepin-4-yl) vinegar in anisole 5d, and the mixture was allowed to stand at room temperature for 3.5 hours. The brown colored solution was moved under reduced pressure, and the residue was dissolved in ethyl acetate IQ1111.
After bathing, 18 s+l of water was added, and while stirring, 1 yam was added to adjust the pH to 7.

After stirring for 5 minutes, the pH was adjusted to 2.7 with 3N hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate.The solvent was distilled off, and the residue was dissolved in methanol-methylene chloride 1.
: 20 silica gel column chromatography,
Crystallization from a small amount of dichloromethylene and isopropyl ether gave the desired compound 0.311.

Melting point: 146-148℃ [α] D-506, 1° (C1, DMF).

NMR (CDCJ3) δ (ppm): 1.16 (3
H, s, C02CH2C5).

1.6 2.2 (2H, m, PhCH2CH2).

2.4-λ9 (2H*rn, PhCH2CH2)
.

3.0-4.62 [8H,C-Cf1(Co2CH,
2CH5)-N.

N-CH2-Co, thiazepine ring 6 and T-position proton].

s, a4 (IHe s, proton at 3-position of thiazepine ring)
.

6.7-7.4 (3H, m, thiophene is proton).

7.14 (SR, S, phenyl group proton).

Example λ α-(s (R) -C1(S)-ethoxycarbonyl-3-phenylpropylami/]-5-oxo-4,5
,6,7-titrahydro-2-(2-chenyl)-1
, 4-+7zebin-4-yl) acetic acid 0.16F in 1N sodium hydroxide water bath solution (1.8 ml) was stirred with fingers at room temperature for 5 hours.
IN hydrochloric acid was added to adjust the pH to 2.7K. The precipitated target compound was collected and air-dried. Yield 125 tq! . Melting point 215-217°C.

[α]D-517° (CI, DMF).

NMR (DMSO-d, 5) δ (ppm): 1
．． 65 2.0 (21,'m, PhCH2CH
2).

7.4-2.11 (2H, m, PhCH2CH2)
.

3G -3,4 (2H1rne CM CH2S).

- 3.5-4.0 (2H, m, PhCH2CH2CH
-N, thiazepine ring 6-position proton).

4.24 (2H, ABq, Δδ=0.33ppm,
J=17Hz.

N CR2Co L 7.0-7.55 (4H, m, thiophene range proton, thiazepine ring 3-position proton).

7.23 (5H, S, phenyl group proton).

Reference example 1゜α-[5-oxo-6@)-phthalimide-2-(2-
-F-enyl)berhydro-1,4-thiazepine-4-
Acetic acid tert-butyl ester 2, Og anhydrous methylene chloride 20 ml.
I added 8 hours little by little. After stirring for 30 minutes at -50°C,
It was brought to room temperature and washed with Kagami 1 water.

After drying with anhydrous magnesium sulfate, remove the common medium.

The residue was subjected to silica gel column chromatography using cyclohexane-ethyl acetate 2:1 as a solvent system to obtain 0.351 of the target compound in the form of a glass.

[α] Sweet 336° (CI, DMF).

NMR (cpcj5) δ (ppm): 1, aa (9
a, at tert-Bu).

3.62 (IH, d, d, J==6.11.5Hz
, -'AsH-s).

4.15 (2H, S, N-CH2-Co).

4.66 (IH, t, J=11.5Hz, -CH
, H-8).

s, 4s < IH, a, d, J=6.11.5Hz
, N-cu-co>.

6.93 (IH, S, >c=cH<).

6.9-7.4 (3Home Thio 7:17B
l proton).

7.6-8.0 (AH, m, phthaloyl group proton).

Example 2 α-[5-okino6(R)-phthalimide-2-(2
-thenyl)berhydro-1,4-thiazepin-4-yl] 6-acid tert-butyl ester 2.36 f-rimethylene chloride m-chloroperbenzoic acid (purity 95% or more) A 30 mt bath 1 of 0.879 methylene chloride was added dropwise. The reaction bath was washed with distilled water for 1 hour, dried over anhydrous magnesium, and the solvent was distilled off to obtain powdered α-[5-okino 6(
R)-phthal(mi)'-2-(2-chenyl)berhydro-1,4-thiazepin-4-yl]acetic acid tert-
2.521 S-oxides of butyl esters were obtained.

0.61 of this compound was bathed in 5 ml of acetic anhydride, and 13
After stirring for 4 hours in an oil bath at 0°C, the solution was worked up under reduced pressure, and the residue was subjected to silica gel column chromatography using cyclohexane-ethyl acetate 2:1 to obtain a glassy solid of 0.10%.
I got f. The optical rotation and NMR spectrum of this solid matched those obtained in Reference Example 1.

Reference example Phester α-[5-oxo-6(R)-phthalimide-4,5,
6,7-titrahydro-2-(2-chenyl)-1,4
-thiazepin-4-yl] hydrazine/
0.44 g+/ of monohydrate was added, and the mixture was stirred at room temperature for 4 days. The precipitate was removed, P solution was added, and the residue was subjected to silica gel column chromatography using ethyl acetate-methanol (10:1) to obtain 0.66 g of the target compound in the form of a gum.

[α”) D-517,5° (C1,0, DMF).

NMR (CDcJ3) δ (ppm): 1.47
(9H,s, tert-butyl).

IJ2 (2H1s, NH2).

3.02 (IH, t, J=IQ, 5Hz, -〇)
I, H-8).

3.64 (i) t, d, d, J=6. IQ, 5
Hz, -CH,H-8).

, - 4,0Q (Im(, d, d, J=6. IQ, 5H
z, N-CH-C0).

4.16 (2H, ABq, Δδ=Q, 42 pprn
*J = IT-5Hz IN-0M2-CO).

6, H(IH,s, ;c=c4':, C6,9-7
,4(3I(,S,thiophene ring proton).

- Example 4 α-C6(R) -tert-butoxycarbonylamino-5-oxo-2-(2-chenyl)berhydro-1
, 4-thiazepin-4-yl] vinegar version tert-butyl ester 500T1g in a toluene Isd bath in a chlorine gas stream at -50°C, 135μ of N-methylmorpholine! ,
Then, 132 μj of tert-,y-thiol hypochlorous acid was added, and the mixture was stirred at -45 to -50°C for 3 hours and briefly at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, washed with water, dried over anhydrous magnesium waxate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography using cyclohexane-ethyl acetate 4:1 as a solvent thread to obtain a glassy target metal 35.
I got 7■.

[α piece -603,5° (CI, DMF).

NMR (CDCJ5) δ (ppm): 1.43 (9
H, s, tert-nu) el, 46 (9) L,
s, tert-flu).

3.13 (IH, t, J==11t(z, -〇,)I-8).

3.82 (11(, d, d, J=5.5Hz, -
C) 1,1(-8).

4.1? (2J ABq, Δδ=0.30ppm,
J=18Hz.

N-C Yu2-co).

4.88 (11I, d, d, d, J=5.5.
B. 11Hz.

N-C)l-Co)t 5.64 (IH, d, J=8Hz, NH).

6.82 (1HIS, 〉C=Cdangu)I6.
9-7.4 (3H, m, thiophene ring proton)
.

Reference example 5゜ ester

Claims (1)

[Claims] ▲ Numerical formulas, chemical formulas, tables, etc. represents a protecting group for an atom or carboxy group, R^3 represents an aryl group or a heterocyclic group,
A represents a lower alkylene group. ) is a tetrahydrothiazepine derivative.