JPH01186875A - Production of benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To produce the title compound useful as a medicine or intermediate therefor, etc., having hypotensive action, etc., by condensing a propionic acid derivative with an N,N-dilower alkylethylenediamine and intramolecularly cyclizing the resultant propionamide derivative. CONSTITUTION:A propionamide derivative expressed by formula I (R<1> is lower alkyl or lower alkoxy; R<2> is H or lower alkanoyl; either of R<3> and R<4> is lower alkyl or Cl and the other is H; R<5> and R<6> are alkyl) X is Br or I) is intramolecularly cyclized to afford the aimed benzothiazepine derivative [e.g., (+ or -)cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chlor o-2,3- dihydro-1,5-benzothiazepin-4(5H)-one] expressed by formula II. The compound expressed by formula I is obtained by condensing a compound expressed by formula III with an N,N-dilower alkylethylenediamine. The resultant product has cerebral-cronary vasodilator and blood platelet inhibitory action.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to -mona (where R1 is a lower alkyl group or a lower alkoxy group,
R2 is a hydrogen atom or a lower alkanoyl group, R3 and R4
One of these represents a lower alkyl group or a chlorine atom and the other represents a hydrogen atom, and Rs and R& represent a lower alkyl group. ) This invention relates to a new method for producing a benzothiazepine derivative.

The benzothiazepine derivative (1) of the present invention is a useful pharmaceutical compound having excellent antihypertensive action, cerebral/coronary vasodilatory action, and/or platelet aggregation inhibiting action. Compounds containing a hydrogen atom are also useful as intermediates for pharmaceutical synthesis of compounds where R: is a lower alkanoyl group.

(Prior Art) Conventionally, as a method for producing the target compound (1), a method is known in which a corresponding N-unsubstituted-1,5-benzothiazepine derivative is reacted with di-lower alkylaminoethyl halide. (Unexamined Japanese Patent Application No. 59-225174, 60-2
No. 02871).

(Structure and Effects of the Invention) According to the present invention, the target compound (1) is
X represents a bromine or iodine atom, Ht.

R1, R3 and R4 have the same meanings as above. ) or a reactive derivative thereof at the carboxyl group is subjected to a condensation reaction with N,N-di-lower alkylethylenediamine to obtain the general formula (however, the symbols have the same meanings as above). After obtaining the propionic acid amide derivative shown, this propionic acid amide derivative (
III) can be produced by intramolecular ring closure.

The condensation reaction of the propionic acid derivative (II) or its reactive derivative in the carboxyl group with N,N-dilower alkylethylenediamine can be carried out by a conventional method for peptide synthesis.
The condensation reaction between the reactive derivative in the carboxyl group of n) and di-lower alkylethylenediamine can be carried out using di- or tri-lower alkylamine, N-lower alkylmorpholine, di-lower alkylaminopyridine, alkali metal bicarbonate, alkali metal carbonate, etc. It can be suitably carried out in the presence of a conventional deoxidizing agent, and as the reactive derivative, for example, acid halides, mixed acid anhydrides, active esters, etc. can all be suitably used. On the other hand, the condensation reaction between free carboxylic acid type propionic acid derivative (II) and N,N-dilower alkylethylenediamine can be carried out using, for example, dicyclohexylcarbodiimide, diethylchlorophosphate, ethoxyacetylene, 1-methyl-2-halo It can be suitably carried out in the presence of a commonly used dehydrating agent such as pyridinium halide or carbonyldiimidazole. All of the above condensation reactions proceed suitably in a suitable solvent that does not participate in the reaction, such as dioxane, toluene, tetrahydrofuran, dimethylformamide, etc., at room temperature or under heating.

The intramolecular ring closure reaction of the propionic acid amide derivative (m) thus obtained can be carried out in the presence of a catalyst and a base. Both copper powder and copper compounds can be suitably used as the catalyst, and examples of the copper compounds used for this purpose include cuprous oxide, cupric oxide, cuprous chloride, cupric chloride, etc. , cuprous bromide, cupric bromide, carbonated steel, etc. In addition, as a base, alkali metal carbonate,
Alkali metal bicarbonate, tri-lower alkylamine, dialkylallylamine, N-lower alkylmorpholine, etc. can be suitably used. The reaction is carried out by heating in a suitable solvent that does not participate in the reaction (e.g., chlorobenzene, toluene, dimethyl sulfoxide, etc.). Proceed appropriately below.

Although the target compound (1) and the starting compound (II) of the present invention have stereoisomerism and optical isomerism based on asymmetric carbon atoms, the reaction of the present invention proceeds without racemization. If an optically active compound is used as the raw material compound (■), the target compound (■) can also be obtained as an optically active compound.

In addition, the raw material compound (n) of the present invention is a thiophenol derivative represented by -Monken (however, the symbol has the same meaning as above) and the general formula (however, R1 has the same meaning as above, R - represents a lower alkyl group) It can be obtained by reacting a glycidic acid ester represented by the formula, hydrolyzing it, and, if desired, 0-acylating it according to a conventional method.

In addition, when this starting compound (I[) is a racemate, its optically active form includes, for example, starting compound (II) in which R1 is a hydrogen atom and optically active 1-(2-naphthylsulfonyl).
It can be obtained by reacting with pyrrolidine-2-carbonyl chloride, dividing the two diastereomers produced using the difference in solubility, hydrolyzing this, and further acylating the 2-position hydroxyl group, if desired.

Example 1 (1) 2.0 g of (±)threo-3-(2-iodo-5-chlorophenyl)thio-3-(4-methoxyphenyl)-2-hydroxypropionic acid in 60 liters of acetic anhydride.
200 mf of water and 100 mf of tetrahydrofuran were added to the reaction solution stirred at ℃ for 2 hours, and after further stirring at room temperature for 1 hour,
The reaction solution was made alkaline with potassium nitrate, further acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure (±)Threo-3-(2-code-5).
-chlorophenyl)thio-3-(4-methoxyphenyl)-2-acetoxypropionic acid is obtained as an oil.

IR(ltq): 3600~2200.1?50
．． 1605. .

1580 c--1 This product was dissolved in dichloromethane 10-, thionyl chloride 4- was added, and the refluxing 0 reaction solution was concentrated under reduced pressure (±).
27 g of threo-3-(2-iodo-5-chlorophenyl)thio-3-(4-methoxyphenyl)-2-acetoxypropionic acid chloride 2 is obtained.

IR(liq): 1795.1760.1610
cm+ -' (2) A 100% dichloromethane solution from the main island was diluted with N,N-dimethylethylenediamine 48% at room temperature.
0■ and triethylamine 570■ dichloromethane 7
〇-Add to solution. The mixture was stirred at room temperature for 1 hour.
After the reaction was completed, it was diluted with ethyl acetate, washed with 5% sodium bicarbonate, washed with water, dried, and concentrated under reduced pressure to give (±)threo-N-(2-(dimethylamino)ethyl)-3-(2
-iodo-5-chlorophenyl)thio-3-(4-methoxyphenyl)-2-acetoxypropionic acid amide 2
．． 48 g are obtained as oil.

I R(liq)': 3330.30?0.2820.
2770.1?50°1670, 1610.1530.
1515 cm -' (3) 2.3 g of the main island was made of iodized steel (
1) Stir under reflux for 2 hours in chlorobenzene with 1.21 g of potassium carbonate and 1.21 g of potassium carbonate. After completion of the reaction, dilute with ethyl acetate, remove inorganic substances by filtration, and wash the filtrate with ethyl acetate. , concentrate under reduced pressure. The oily residue was purified by silica gel column chromatography (CHCIs: Btoll, 20
:1), convert it into a hydrochloride, and recrystallize it from ethanol-ethyl ether to give (±)cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl-8- Chloro-2゜3-dihydro-1,5
-Benzothiazepine-4(5H)-one hydrochloride 1.5
Obtain 3g.

mp, 159-161°C Yield 79.4% Example 2 (1) (+)threo-3-(2-iodo-5-chlorophenyl)thio-3-(4-methoxyphenyl)-2-hydroxypropionic acid 1.9 g in 1ONi of acetic anhydride
Stir at 0°C for 2 hours. The reaction solution was prepared as shown in Example 1-(1) below.
By processing in the same way as (+)-threo-3-(
2-iodo-5-chlorovinyl)thio-3-(4-methoxyphenyl)-2-acetoxypropionic acid.
Obtain 0.7g.

[α)”; −69,7° (C-0,83, chloroform) IR (COCl2): 1750.1
? 15. 1640. 1600 cm -' Main Island was then dissolved in 10 yd of dichloromethane, thionilk and loride 4- were added, and the mixture was refluxed for 2 hours. By concentrating the reaction solution under reduced pressure, (+)-threo-3-(2-:
i? 2.15 g of -5-chlorophenyl)thio-3-(4-methoxyphenyl)-2-acetoxypropionic acid chloride are obtained as an oil.

(2) Main island 2.15g of dichloromethane 100-liquid,
In addition to a solution of 480 g of N,N-dimethylethylenediamine and 570 g of triethylamine in 60 g of dichloromethane, the following treatment was carried out in the same manner as in Example 1-(21).
(+)threo-N-(2-(dimethylamino)ethyl)
-3-(2-iodo-5-chlorophenyl)thio-3-
2.35 g of (4-methoxyphenyl)-2-acetoxypropionic acid amide is obtained as an oil.

[α) o-80,2@(C-0,41, chloroform) ~ Summer R(liq): 3320. 307
0. 2930. 2850. 2B30°2760,
1?40. 1660. 1600. 1575°1
505 ca+ -' (3) Add 4.1 g of Honjima, 100 g of copper (1) iodide, and 2.6 g of potassium carbonate to 50 - of chlorobenzene, and stir under reflux for 3 hours. The reaction solution was treated in the same manner as in Example 1-(3) and recrystallized from ethanol as a maleate salt to obtain (+)cis-2-(4-methoxyphenyl)-
3.35 g of 3-acetoxy-5-[2-(dimethylamino)ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H)-one maleic acid are obtained.

mp, 158-160°C Yield 83.4% Example 3 (±)threo-N-(2-(dimethylamino)ethyl)-3-(2-iodo-5) obtained in Example 1-(2) -chlorophenyl)thio-3-(4-methoxyphenyl)-2
-Acetoxypropionic acid amide 1. Dissolve Og in dimethyl sulfoxide 101111 and toluene 10-,
Copper iodide (1) 25■.

Add 520+r of potassium carbonate and stir at 110°C for 2 hours. After completion of the reaction, dilute with ethyl acetate, remove inorganic substances by filtration, and condense the filtrate under reduced pressure. The oily residue was purified by silica gel column chromatography (CHCh:HtOH, 20:1), converted into a hydrochloride salt, and recrystallized from chlorokymethanol-ether to give (±)cis-2-(4-methoxyphenyl)-3- 410 w of acetoxy-5-(2-(dimethylamino)ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride) is obtained.

mp, 159-161°C Yield 48.7% Examples 4-8 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Examples 1-3.

(4) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-(dimethylamino)
Ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H)-mp, 123-125
°C (5) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-(dimethylamino)
ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H)-one perchlorate 1/4
Hydrate m1190-192℃ (6) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)
Ethyl]-9-chloro2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride monohydrate mp, 140-143°C (7) (±)-cis-2- (4-methylphenyl)
-3-hydroxy-5-(2-(dimethylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one mp, 142-143°C
(Recrystallized from ethyl acetate) (8) (±)-cis-2
-(4-methylphenyl)-3-acetoxy-5-(2
-(dimethylamino)ethyl-8-methyl-2,3-
Dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride: mp, 190-192°C (recrystallized from a mixture of acetone and isopropyl ether) mp, 184-1
86℃ (recrystallized from a mixture of isopropanol and ether) Fumarate: m
p, 196.5-198.5°C (decomposed) (recrystallized from propatool) Maleate: mp, 172.5-17
4℃ (recrystallized from methanol) mp, 191.9℃ (recrystallized from water) Methanesulfonate: mp, 124-128℃ (recrystallized from propatool) (9) (+)-cis-2-( 4-methylphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one maleate: mp,
194-197℃ (decomposition) (recrystallized from ethanol) (α) +83.7℃ (C proverb 0.362.methanol)
Shellate salt: mp, 179-180°C (recrystallized from ethanol) [α]. +88.2° (C-0,288, methanol) (10) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-(2-(dimethylamino)ethylgo8-methyl-2 ,3-dihydro-1,5-
Benzothiazepine-4(5H)-one maleate: m
p, 195-197.5°C (decomposed) (recrystallized from ethanol) [α]. -83,6° (C-0,50, methanol)
Shellate: mp, 179.5-181℃ (decomposed) (recrystallized from ethanol) Snow/[α)D -83,8" (C=0.333.methanol) Fumarate: mp, 210.5 ~212.5℃
(Decomposition) (Recrystallized from ethanol) [α] ■ -91,3@(C-0,323, methanol) L-(+)-ciesteric acid: mp, 140-143°C (mixture of ethanol and diethyl ether Reference Example 1 (1) A mixture of 10 g of 5-chloro-2-iodobenzenesulfonic acid sodium salt, 10 g of phosphorus pentachloride, and 5-phosphorus oxychloride was stirred at room temperature to 50° C. After the reaction was completed,
The mixture was concentrated under reduced pressure and the residue was recrystallized from n-hexane to give 5-chloro-2-iodobenzenesulfonyl chloride 8.
．． Obtain 66g.

mp, 66-68°C 8.56 g of Oshima is added to a mixture of ice and concentrated sulfuric acid (9.47 g), 8.46 g of lead powder is added in a water-cooled saucepan, and the mixture is refluxed. Zinc dust was added, left to cool, extracted with toluene, and the extract was concentrated under reduced pressure to obtain 3.4 g of 5-chloro-2-iodothiophenol.
is obtained as an i-form product.

(2) Main island 1.7 g,) lance-3-(4-methoxyphenyl)glydiphthoic acid methyl ester 1°5 g and 2-
A toluene solution of 2 drops of tin ethylhexanoate (■) was stirred. The reaction solution was condensed under reduced pressure, the residue was purified by silica gel column chromatography, and recrystallized from ether-hexane to obtain (±)threo-3-(2 1.8 g of -g-do-5-chlorophenyl)thio-3-(4-methoxyphenyl)-2-hydroxypropionic acid methyl ester are obtained.

mp, 66-68℃ IR(liq): 3480.1740.1605
cm-'' was added to a methanol solution of sodium hydroxide, stirred at room temperature, and extracted with ether under acidic conditions. The solvent was distilled off from the extract, and the residue was recrystallized from ethyl acetate-isopropyl ether ( ±)Threo-3-(2
-iodo-5-chlorophenyl)thio-3-(4-methoxyphenyl)-2-hydroxypropionic acid 1.07
get g.

mp, 168-169°C IR (Nujol): 3470.3200-21
00.1700°1600 cm-' Reference Example 2 (1) (±)Threo-3-(2-iodo-5-chlorophenyl)thio-3-(4-methoxyphenyl)-2-
t: Add 4.95 g of (S)-1-(β-dinaphthalenesulfonyl)pyrrolidine-2-carbonyl chloride to a pyridine solution of 6.7 g of droxyprobionic acid under water cooling, and stir. Add ethyl acetate and water to the reaction solution. Add. The organic layer was separated under acidic conditions, the solvent was distilled off, and the residue was separated using silica gel chromatography to obtain (2S, 3S) -3-(4-
4.45 g of methoxyphenyl)-3-(2-iodo-5-chlorophenyl)thio-2-((S)-1-(2-naphthalenesulfonyl)-pyrrolidine-2-carbonyl)oxypropionic acid (product A) and its (2R, 3
4.73 g of R)-isomer (product B) are obtained.

(2) Add 4.45 g of the above product A to a water/methanol solution of potassium carbonate, stir at room temperature, and then extract the reaction solution with chloroform under acidic conditions. The solvent was distilled off from the extract, and the residue was purified by silica gel chromatography to obtain (+)-threo-3.
-(4-methoxyphenyl)-3-(2-iodo-5-
chlorophenyl)thio-2-hydroxypropionic acid 2
．． 32 g are obtained as an oil.

(αl o +94.5 @(C”0.40. THF
) I R (Nujol): 3300 (broad),
1710°1610, 1580 cge -
Additionally, product B was treated in the same manner as above to give (-)-threo-3-(4-methoxyphenyl)-3-(2-iodo-
5-chlorophenyl)thio-2-hydroxypropionic acid is obtained as an oil.

[α)! + -108,8" (C・1.84.・THF
) I R (Nujol): 3300 (broad),
1710.1610°1580 cm-' Voluntary procedure amendment 1. Display of the case Patent Application No. 9408 of 1988 2, Name of the invention Process for producing benzothiazepine derivatives 3, Person making the amendment Relationship to the case Patent applicant Zip code 541 3-2 Doshomachi, Chuo-ku, Osaka-shi, Osaka Prefecture No. 1O (Address change on February 13, 1989) (295) Tanabe Pharmaceutical Co., Ltd. 3-16-89 Kashima, Yodogawa-ku, Osaka-shi, Osaka (Location 06)
-300-2723 or 2724 Patent Office) 5, Detailed description of the invention column 6 of the specification subject to amendment, Contents of the amendment (1) "Potassium nitrate" in lines 7-8 on page 10 of the specification has been replaced with "potassium carbonate" ” is corrected.

(2) Page 13, line 1 r-69,7°” r　+69.7　”　Corrected to J.

(3) 1st row from the bottom of No. 13 r-80,2°” Corrected to “r　+80.2°”.

(4)　Page 22, line 9 "[α]D" Correct it to “[α]■”.

Claims (2)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ (However, R^1 is a lower alkyl group or lower alkoxy group, R^2 is a hydrogen atom or lower alkanoyl group, R^3 and R^4 are either One is a lower alkyl group or a chlorine atom, the other is a hydrogen atom, R^5 and R^6 are a lower alkyl group, and X represents a bromine or iodine atom. A method for producing benzothiazepine derivatives represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, the symbols have the same meanings as above.) (2) General formula▲ Numerical formula, chemical formula, table, etc.▼ (However, R^1 is a lower alkyl group or lower alkoxy group, R^2 is a hydrogen atom or lower alkanoyl group, R^3 and R^4 are either one is a lower alkyl group or a chlorine atom, the other is a hydrogen atom, and X represents a bromine or iodine atom) or its reactive derivative in the carboxyl group; A condensation reaction with lower alkyl ethylene diamine produces the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^5 and R^6 represent lower alkyl groups, and R
^1, R^2, R^3, R^4 and X have the same meanings as above. ) After obtaining the propionic acid amide derivative, this propionic acid amide derivative is subjected to intramolecular ring closure. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (However, the symbols have the same meanings as above. ) A method for producing a benzothiazepine derivative.