JPS6345675B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to benzothiazepine derivatives, more particularly to benzothiazepine derivatives of the formula The present invention relates to a new industrially advantageous method for producing the optically active cis-benzothiazepine derivative shown in the following. Conventionally, the method for producing this compound has been to 2-(p-methoxyphenyl)-3-hydroxy-2.3-dihydro-1.5-benzothiazepine-4(5H)one,
It is synthesized by a method of reacting an alkali metal, its hydride, or its amide, reacting it with N,N-dimethylaminoethyl chloride, and then acetylating it. (Tokuko Showa 46-43785
However, this is not necessarily an industrially safe method in that it uses alkali metals, their hydrides, or amides. In other words, since these metal compounds are dangerous compounds that react extremely violently with water, constant attention must be paid to the danger of fire at the site where they are handled, and handling and reaction equipment must be specialized. be. The present invention is an industrially advantageous method in that it does not use any such highly dangerous raw materials. Furthermore, the method of the invention can be used as a starting material for the formula [In the formula, X represents a halogen atom and R represents a lower alkyl group. ] It was discovered that the optically active erythro compound represented by the formula and the subsequent reaction intermediate compounds are all new compounds, and that they can be derived into the target compound without racemization in the subsequent reaction process, and formula [In the formula, It has its characteristics in the points discovered. Next, the present invention will be explained step by step. The present invention consists of the following three steps. That is, (1) Equation () [In the formula, X and R are the same as above] Optically active -erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-
Halogenophenylthio)-propionate is reacted with N,N-dimethylethylenediamine without a solvent or in an appropriate solvent to obtain the formula () [In the formula, X is the same as above] Optically active -erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-
(p-methoxyphenyl)-3-(o-halogenophenylthio)-propionic acid amide is obtained.
When a solvent is used, any solvent that does not participate in the reaction, such as dioxane, toluene, xylene, tetrahydrofuran, dimethylformamide methanol, and ethanol, can be used without any problem. The reaction is carried out at room temperature to 120°C, preferably 60°C to
The process can be suitably carried out at 100°C. (2) The optically active -erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyphenyl)-3-(o-halogenophenyl) represented by the formula () thus obtained (ruthio)-propionic acid amide is acetylated in an appropriate solvent, and the formula () [In the formula, X is the same as above] Optically active -erythro-N-(β-dimethylaminoethyl)-2-acetoxy-3-
(p-methoxyphenyl)-3-(o-halogenophenylthio)-propionic acid amide is obtained.
Examples of the acetylation reagent used here include acetic anhydride, acetic acid, or reactive derivatives thereof (eg, acetyl chloride, acetyl bromide, mixed acid anhydrides, esters, etc.). The solvent to be used may be one that does not participate in the reaction, but aromatic hydrocarbons such as benzene, chlorobenzene, toluene, and xylene, ketones such as acetone and methyl ethyl ketone, isopropyl ether, dioxane, and tetrahydrofuran, etc. Examples include ether chloroform, halogenated hydrocarbons such as methylene chloride, and esters such as ethyl acetate and butyl acetate. The novel compound represented by the formula () thus obtained is isolated or used in the next reaction without being isolated. (3) Thus, the optically active -erythro-N-(β-dimethylaminoethylamino) represented by the formula ()
-2-acetoxy-3-(p-methoxyphenyl)-3-(o-halogenophenylthio)-propionic acid amide is heated in an appropriate solvent in the presence of copper powder or a copper compound and a base to undergo a ring-closing reaction. be done. Here, the solvent may be the one used in the acetylation reaction,
The type does not matter as long as it is not involved in the reaction. Copper compounds include cuprous oxide, cupric oxide, cuprous chloride, cupric chloride, cuprous bromide, cupric bromide, cuprous added, cupric added, and copper carbonate. Examples include. Bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine,
Examples include organic bases such as N-methylmorpholine. The reaction temperature is suitably carried out in the range of 80 to 180°C. Thus, the compound represented by formula () has a closed ring and an optically active -3-acetoxy-cis-2.3-dihydro-5-(β-dimethylaminoethyl)-2-(p-methoxyphenyl)-1.5-benzo Gives thiazepin-4(5H)-one. Among the objective compounds of the present invention thus obtained,
(+)-3-acetoxy-cis-2.3-dihydro-5-(β-dimethylaminoethyl)-2-(p
BACKGROUND ART -Methoxyphenyl)-1,5-benzothiazepine-4(5H)-one or its hydrochloride is a compound that has a coronary vasodilator effect and is used as a medical therapeutic agent. The raw material compound (represented by formula ()) used in the present invention is produced according to the method for producing optically active propionic acid derivatives, which is the title of the invention filed on the same date by the same applicant as the present invention. ``In the description of this specification, the expression ``erythro'' used in determining the steric configuration of a compound is an expression for a compound having the structure shown below in accordance with Fischer's projection method. (Reference Chem.Pharm.Bull., 18, 2284
(1970))

[Formula] or

[Formula _] [ _Wherein , The invention will now be described in further detail. Example 1 (a) (+)-erythro-2-hydroxy-3-(p
-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid methyl ester 6.37 g,
A mixture of 2.53 g of N,N-dimethylethylenediamine was stirred at 85°C for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated, isopropyl ether was added to the residue, and the precipitated crystals were collected (+)-
Erythro-N-(β-dimethylaminoethyl)-
2-hydroxy-3-(p-methoxyphenyl)
-3-(o-iodophenylthio)-propionic acid amide was obtained. Amount obtained: 5.97 g (yield: 83.2%) The obtained crystals were dissolved in chloroform to form a hydrochloride, and recrystallized from chloroform to obtain the compound hydrochloride as scaly white crystals. Yield 4.12g Melting point 97-99.5℃, TLC (chloroform:methanol:acetic acid = 20:4:3V/V) single spot, IR spectrum cm ^-1 : 3300 (OH), 2650 (-N ⁺ H)
1670 (amide) Specific rotation [α] ^22.5 _D = +77.0° (C = 1.0 water) NMRδ ^DMSO-d6 _TMS : 2.72 (6H, s, N(CH ₃ ) ₂ ),
3.65 (3H, s, OCH ₃ ), 4.1~4.45 (m), 4.79
(d) (1H, C ₂ -H, 1H, C ₃ -H), 6.22
(1H, d, OH) (b) (+)-Erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio) −
3 g of propionic acid amide hydrochloride was suspended in ethyl acetate and made slightly alkaline with dilute aqueous sodium bicarbonate solution. The organic layer was separated, washed with water, dried, and concentrated. Add isopropyl ether to collect crystals, and (+)-erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)
- 2.03 g of white crystals of propionic acid amide were obtained. mp 71-74℃ TLC (chloroform: methanol: acetic acid =
20:4:3V/V): Single spot IRcm ^-1 : 3320 (OH), 1660 (amide), Specific rotation [α] ^22.5 _D = +91.5° (C = 1.0 methanol) NMRδ ^CDCl3 _TMS : 2.0 (6H, s, N(CH ₃ ) ₂ ), 2.33
(2H, t, C〓−H ₂ ), 3.23 (2H, q, Cα−
H ₂ ), 3.72 (3H, s, OCH ₃ ), 4.41, 4.86
(1H, d, C ₂ -H, 1H, d, C ₃ -H) Example 2 (a) In Example 1 (a), (+)-erythro-2-
Hydroxy-3-(p-methoxyphenyl)-3
-(o-iodophenylthio)-propionic acid methyl ester instead of (-)-erythro-2-
Hydroxy-3-(p-methoxyphenyl)-3
Using 10 g of -(o-iodophenylthio)-propionic acid methyl ester, (-)-erythro-N-(β-dimethylaminoethyl)-2
-Hydroxy-3-(p-methoxyphenyl)-
White crystals of 3-(o-iodophenylthio)-propionic acid amide were obtained. Amount obtained: 9.1 g (yield: 80.8%) The obtained crystals were similarly converted to hydrochloride to obtain the hydrochloride of the compound as scaly white crystals. Yield 9.76g mp 97-99℃ TLC (chloroform:methanol:acetic acid=
20:4:3V/V): Single spot IRcm ^-1 : 3280 (OH), 2650 (-N ⁺ H), 1670 (amide) Specific rotation [α] ^22.5 _D = -77.1° (C = 1.0 water ) NMRδ ^DMSO-d6 _TMS : 2.7 (6H, s, N(CH ₃ ) ₂ ), 3.63
(3H, s, OCH ₃ ), 4.1~4.45(m), 4.78(d)
(1H, C ₂ -H, 1H, C ₃ -H), 6.22 (1H,
d, OH) (b) Example 1 using 8.05 g of the hydrochloride obtained in (a)
Process in the same manner as (b), and (-)-erythro-N-
White crystals of (β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide were obtained. Yield 5.54g mp 70-73℃ TLC (chloroform:methanol:acetic acid=
20:4:3V/V): Single spot IRcm ^-1 : 3320 (OH), 1660 (amide) Specific rotation [α] ^23.5 _D = -91.2° (C = 1.0, methanol) NMRδ ^CDCl3 _TMS : 2.01 ( 6H, s, N(CH ₃ ) ₂ ), 2.32
(2H, t, C〓−H ₂ ), 3.23 (2H, q, C〓−
H ₂ ), 3.72 (3H, s, OCH ₃ ), 4.4, 4.87 (1H,
d, C ₂ -H, 1H, d, C ₃ -H) Example 3 (a) (+)-Erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyphenyl )-3-(o-iodophenylthio)-
9.3 g of propionic acid amide, 2.28 g of acetic anhydride,
A mixture of 80 ml of toluene was stirred at 70-80°C for 2 hours. The reaction mixture was poured into ice water and the organic layer was separated. The organic layer was washed with water, dried, and concentrated to give a candy-like (+)-erythro-N-(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o-iodo phenylthio)
-Propionic acid amide was obtained. The amount obtained was 9.99 g, yield 99.0%, and this product showed a single spot on TLC (chloroform: methanol: acetic acid = 20:4:3 V/V). 4 g of the candy-like compound thus obtained was converted to the hydrochloride salt in ether, and (+)-erythro-N-(β-
dimethylaminoethyl)-2-acetoxy-3
White powder crystals of -(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide hydrochloride were obtained. Yield 4.08g mp 85-88℃ TLC (chloroform:methanol:acetic acid=
20:4:3V/V) single spot, IRcm ^-1 : 2600, 2450 (-NH), 1745 (ester), 1675 (amide) Specific optical rotation [α] ²⁰ _D = +59.0° (C = 1.0 water) NMRδ ^CDCl3 _TMS : 2.15 (3H, s, -COCH ₃ ), 2.77
(6H, s, -N(CH3) ₂ ), _2.4-4.0 (4H, m,
NCH ₂ CH ₂ N), 3.68 (3H, s, O-CH ₃ ),
4.95, 5.49 (1H, d, C ₂ −H, 1H, d, C ₃ −
H), 6.5-7.9 (8H aromatic ring hydrogen), 8.42 (1H,
t, NH) (b) 2 g of the hydrochloride obtained in (a) was suspended in ether and made slightly alkaline with dilute aqueous sodium bicarbonate solution. The organic layer was separated, washed with water, dried, and concentrated.
White foamy crystals of (+)-erythro-N-(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide Obtained. Yield: 1.68g TLC (Chloroform: Methanol: Acetic acid =
20:4:3V/V) Single spot IRcm ^-1 : 1740 (ester), 1660 (amide),
1610 (benzene ring) NMRδ ^CDCl3 _TMS : 2.01 (3H, s, -COCH ₃ ), 2.09
(6H, s, N(CH ₃ ) ₂ ), 2.27 (2H, t, C〓−
H ₂ ), 3.1 (2H, g, C〓−H ₂ ), 4.75, 5.34
(1H, d, C ₂ -H, 1H, d, C ₃ -H), 6.1
~7.8 (9H, aromatic ring hydrogen, NH), specific optical rotation [α] ²⁰ _D = +71.6° (C = 1.0 methanol) Example 4 (a) In Example 3, (+)-erythro-N-
In place of (β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide, 15 g of the levorotatory form of the same compound was used, and the same to give a candy-like (-)-erythro-N-(β
-dimethylaminoethyl)-2-acetoxy-
3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide was obtained.
Amount obtained: 16.05 g, yield 98.6%. This product showed a single spot on TLC (chloroform: methanol: acetic acid = 20:4:3 V/V). 5 g of the compound thus obtained were converted into the hydrochloride salt in ether. The crystals were collected and (-)-erythro-N-(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-
White powder crystals of (o-iodophenylthio)-propionic acid amide hydrochloride were obtained. Yield 5.05g mp 85-87℃ TLC (chloroform:methanol:acetic acid=
20:4:3V/V) Single spot IRcm ^-1 : 2600, 2470 (-N+H), 1745 (ester), 1675 (amide) NMRδ ^DMSO-d6 _TMS : 2.04 (3H, s, COCH ₃ ), 2.66
(6H, s, N(CH ₃ ) ₂ ), 3.65 (3H, s,
OCH ₃ ), 5.04, 5.32 (1H, d, C ₂ -H, 1H,
d, _C3 -H), 6.3-7.9 (8H, aromatic ring hydrogen),
8.63 (1H, t, NH) Specific optical rotation [α] ²⁰ _D = -60.7° (C = 1.0 water) (B) 2 g of the hydrochloride obtained in (B) was suspended in ether and diluted with dilute aqueous sodium bicarbonate solution. It was made slightly alkaline. The organic layer was separated, washed with water, dried, and concentrated to give (-)-erythro-N-(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o- iodophenylthio)
-White foam crystals of propionic acid amide were obtained. Yield: 1.70g TLC (Chloroform: Methanol: Acetic acid =
20:4:3V/V) Single spot IRcm ^-1 : 1750 (ester), 1670 (amide),
1610 (benzene return) Specific rotation [α] ²⁰ _D = -72.7° (C = 1.0 methanol) NMRδ ^CDCl3 _TMS : 2.03 (3H, s, COCH ₃ ), 2.11
(6H, s, N(CH ₃ ) ₂ ), 2.20 (2H, t, C〓−
H ₂ ), 3.13 (2H, q, C〓−H ₂ ), 3.64 (3H,
s, _OCH3 ), 4.82, 5.42 (1H, d, C2 _- H,
1H, d, _C3 -H), 6.1-7.8 (9H, aromatic ring hydrogen, NH) Example 5 The candy-like (+)-erythro-N obtained in Example 3
-(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide 1.08, cuprous iodide 0.02g, anhydrous potassium carbonate A mixture of 0.55 g of chlorobenzene and 10 ml of chlorobenzene was refluxed for 3 hours in a nitrogen atmosphere while removing by-produced water. Insoluble materials were separated, washed with water, dried, and then concentrated under reduced pressure. The residue was derivatized into the hydrochloride salt in ethanol. The precipitated crystals were collected and (+)-3-acetoxy-cis-2.3
-dihydro-5-(β-dimethylaminoethyl)-
2-(p-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one hydrochloride was obtained. Gain 0.72
g, yield 80.0%, which was recrystallized from ethanol.
0.58g of crystals were obtained. mp 211～214゜ TLC (chloroform: methanol: acetic acid =
20:4:3V/V) Single spot IRcm ^-1 : 2400 (-N+H), 1750 (ester),
1680 (amide), 1610, 1520 (benzene ring), Specific rotation [α] ²² _D = +116° (C = 1.0 water) NMRδ ^CDCl3 _TMS : 1.84 (3H, s, -COCH ₃ ), 2.85
(6H, s, N(CH ₃ ) ₂ ), 3.75 (3H, s,
OCH ₃ ), 4.95, 5.1 (1H, d, C ₂ −H, 1H,
d, _C3 -H), 6.6-7.9 (9H aromatic ring, N+H) Example 6 In Example 5, instead of chlorobenzene,
Treat in the same manner using 10 ml of butyl acetate to obtain (+)-3
-acetoxy-cis-2,3-dihydro-5-(β-
Dimethylaminoethyl)-2-(p-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one hydrochloride was obtained. The obtained amount was 0.56 g, yield 62.2%, and this was recrystallized from ethanol to obtain 0.45 g. mp 211-213℃ TLC (chloroform: methanol: acetic acid = 20:
4:3V/V) Single spot IR and NMR were completely consistent with those obtained in Example 5. Specific optical rotation [α] ²² _D = +115.9° (C = 1.0
water) Example 7 Candy-like (-)-6 erythro- obtained in Example 4
N-(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide 1.08 g
The reaction was carried out in the same manner as in Example 5. (-)-3-
Acetoxy-cis-2,3-dihydro-5-(β-dimethylaminoethyl)-2-(p-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one hydrochloride was obtained. The obtained amount was 0.71 g, yield 78.9%, and this was recrystallized from ethanol to obtain 0.57 g. mp 210-212℃ TLC (chloroform: methanol: acetic acid = 20:
4:3V/V) Single spot IRcm ^-1 : 2400 (-N+H), 1745 (ester), 1680
(amide), 1610, 1515 (benzene ring), specific optical rotation [α] ²² _D = -116.6° (C = 1.0 water) NMRδ ^CDCl3 _TMS : 1.91 (3H, s, -COCH ₃ ), 2.91 (6H,
s, N(CH ₃ ) ₂ ), 3.82 (3H, s, OCH ₃ ), 4.98,
5.13 (1H, d, C ₂ -H, 1H, d, C ₃ -H), 6.5
~7.9 (9H, aromatic ring hydrogen, N+H) Example 8 (+)-erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodo A mixture of 2 g of phenylthio)-propionic acid amide, 0.53 g of 93% pure acetic anhydride, and 15 ml of chlorobenzene was stirred at 75° C. for 1 hour. 1.33 g of powdered anhydrous potassium carbonate was added, and the mixture was stirred at the same temperature for 2 hours. Next, powdered anhydrous potassium carbonate
Add 1.10 g and mg of cuprous iodide in a nitrogen atmosphere.
The mixture was heated under reflux for 1.5 hours while removing by-produced water. Insoluble matter was separated, washed with water and dried, and then passed through hydrochloric acid gas to obtain a hydrochloride. The precipitated crystals were collected, washed with isopropyl ether, and (+)-3-acetoxy-cis-2.3-
Dihydro-5-(β-dimethylaminoethyl)-2
-(p-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one hydrochloride was obtained. Yield: 1.44g,
Recrystallization from ethanol yielded 1.16 g with a yield of 80.0%. mp 211-213℃ TLC (chloroform: methanol: acetic acid = 20:
4:3) Single spot, IR and NMR were completely consistent with those obtained in Example 5. Specific optical rotation [α] ^22.5 _D = +116° (C = 1.0 water) Example 9 In Example 8, (+)-erythro-N-(β
-dimethylaminoethyl)-2-hydroxy-3
In place of -(p-methoxyphenyl)-3-(o-iodophenylthio)-propionic acid amide, 5 g of the levorotatory form of the same compound was used, and the same reaction treatment was carried out. (−)-3-acetoxy-cis-2.3-dihydro-5-(β-dimethylaminoethyl)-2-(p
-methoxyphenyl)-1,5-benzothiazepine-
4(5H)-one hydrochloride was obtained. Amount obtained: 3.89g, yield
86.2%, recrystallized from ethanol, 3.32g
I got it. mp 210-212℃ TLC (chloroform: methanol: acetic acid = 20:
4:3V/V) Single spot IR and NMR were completely consistent with those obtained in Example 7. Specific optical rotation [α] ²² _D = -115° (C = 1.0 water) Example 10 (+)-Erythro-2-hydroxy-3-(p-
methoxyphenyl)-3-(o-bromphenylthio)-propionic acid methyl ester 9.93 g, N,
A mixture of 4.41 g of N-dimethylethylenediamine
Stirred at 80-90°C for 3 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, dried, concentrated, and isopropyl ether was added to the residue, and the crystals were collected by filtration to give (+)-erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-(p -methoxyphenyl)-3-
(o-bromphenylthio)-propionic acid amide
9.27g (yield 81.7%) was obtained. 1,1,2,2-
Recrystallized from tetrachlorethylene. mp 85-87℃ [α] ²² _D = +107.7゜ (c = 1.0 methanol) IRcm ^-1 : 3330 (OH), 1670 (amide), 1610 (benzene ring) NMRδ ^CDCl3 _TMS : 2.01 (6H, s, N( _CH3 ) ₂ ), 2.34
(2H, t, C〓−H ₂ ), 3.25 (2H, q, C〓−H ₂ ),
3.71 (3H, s, OCH ₃ ), 4.40, 4.09 (1H, d,
C ₂ -H, 1H, d, C ₃ -H) Example 11 In Example 10, (+)-erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-
(−)-erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid methyl ester instead of bromophenylthio)-propionic acid methyl ester
Amidation was carried out in the same manner using 11.92 g. (−)−
Erythro-N-(β-dimethylaminoethyl)-2
-Hydroxy-3-(p-methoxyphenyl)-3
11.53 g (yield: 84.8%) of white crystals of -(o-bromphenylthio)-propionic acid amide was obtained. 1,
It was recrystallized from 1,2,2-tetrachloroethylene. mp 88-89℃ [α] ²² _D = -108.4゜ (c = 1.0 methanol) IRcm ^-1 : 3330 (OH), 1670 (amide), 1610 (benzene ring) NMRδ ^CDCl3 _TMS : 2.0 (6H, s, N ( _CH3 ) ₂ ), 2.30(2H
,
t, C〓−H ₂ ), 3.21 (2H, q, C〓−H ₂ ), 3.70
(3H, s, OCH ₃ ), 4.38, 4.88 (1H, d, C ₂ −
H, 1H, d, C ₃ -H) Example 12 (+)-Erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyphenyl)-3-(o-bromo A mixture of 4.53 g of phenylthio)-propionic acid amide, 1.32 g of 93% acetic anhydride, and 30 ml of benzene was stirred at 70 to 75°C for 1 hour.
30 ml of ice water was added to the reaction mixture, and the pH was adjusted to 2 with dilute hydrochloric acid, and the aqueous layer was separated. Add benzene again, make weakly alkaline with sodium bicarbonate under cooling, separate the organic layer, wash with water, dry, and concentrate to give a candy-like (+)-erythro-N-(β-dimethylaminoethyl)-2-
Acetoxy-3-(p-methoxyphenyl)-3-
(o-bromphenylthio)-propionic acid amide
4.82g (yield 97.4%) was obtained. [α] ²⁶ _D = +86.2゜ (c = 1.0 methanol) IRcm ^-1 : 1750 (ester), 1670 (amide), 1610
(Benzene ring) NMRδ ^CDCl3 _TMS : 2.0 (3H, s, COCH ₃ ), 2.09 (6H,
s, N(CH ₃ ) ₂ ), 2.20 (2H, t, C〓−H ₂ ), 3.15
(2H, q, C〓−H ₂ ), 3.65 (3H, s, OCH ₃ ),
4.91, 5.46 (1H, d, C ₂ −H, 1H, d, C ₃ −
H) (+)-Erythro-N as hydrochloride in ether
Strongly hygroscopic white crystals of -(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid amide hydrochloride were obtained. [α] ²⁰ _D = +71.7° (c = 1.3 water) IRcm ^-1 : 2670, 2470 (-N + H), 1740 (ester),
1665 (amide), 1605 (benzene ring) NMRδ ^DMSO-d6 _TMS : 2.05 (3H, s, COCH ₃ ), 2.71
(6H, s, N(CH ₃ ) ₂ ), 3.66 (3H, s,
OCH ₃ ), 5.18, 5.40 (1H, d, C ₂ −H, 1H,
d, _C3 -H), 8.8 (1H, t, -CONH-), 10.8
~11.6 (1H, broad, N+H) Example 13 In Example 12, (+)-erythro-N-(β-
dimethylaminoethyl)-2-hydroxy-3-
(-)- instead of (p-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid amide
Erythro-N-(β-dimethylaminoethyl)-2
-Hydroxy-3-(p-methoxyphenyl)-3
Acetylation was carried out in the same manner using 4.53 g of -(o-bromphenylthio)-propionic acid amide. 4.82 g of candy-like (-)-erythro-N-(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid amide ( A yield of 97.4% was obtained. [α] ²⁷ _D = -87.3゜ (c = 1.0 methanol) IRcm ^-1 : 1750 (ester), 1670 (amide), 1610
(Benzene ring) NMRδ ^CDCl3 _TMS : 2.01 (3H, s, COCH ₃ ), 2.10 (6H,
s, N(CH ₃ ) ₂ ), 2.22 (2H, t, C〓−H ₂ ), 3.16
(2H, q, C〓−H ₂ ), 3.68 (3H, s, OCH ₃ ),
4.90, 5.44 (1H, d, C ₂ −H, 1H, d, C ₃ −
H) (-)-Erythro-N as hydrochloride in ether
Strongly hygroscopic white crystals of -(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid amide hydrochloride were obtained. [α] ²⁰ _D = -72.0° (c = 1.4 water) IRcm ^-1 : 2680, 2470 (-N + H), 1735 (ester),
1660 (amide), 1605 (benzene ring) NMRδ ^DMSO-d6 _TMS : 2.05 (3H, s, COCH ₃ ), 2.70
(6H, s, N(CH ₃ ) ₂ ), 3.65 (3H, s,
OCH ₃ ), 5.15, 5.39 (1H, d, C ₂ -H, 1H,
d, _C3 -H), 8.78 (1H, t, -CONH-),
10.7-11.3 (1H, broad, N+H) Example 14 Candy-like (+)-erythro-N-(β-dimethylaminoethyl)-2-acetoxy-3-(p-methoxyphenyl)-3-(o -bromphenylthio)
- 4.77 g of propionic acid amide, 55 g of cuprous iodide
mg, powdered anhydrous potassium carbonate 2.65g, chlorobenzene 45
The ml mixture was refluxed for 3.5 hours in a nitrogen atmosphere to remove by-product water. Insoluble matters were removed by filtration, washed with water, dried, and then passed through hydrochloric acid gas to form a hydrochloride. The precipitated crystals were collected by filtration and washed with acetone. Subsequently, it was recrystallized from ethanol to give (+)-3-acetoxy-cis-2,3-dihydro-5-(β-dimethylaminoethyl)-2-(p-
2.48 g (yield 57.3%) of methoxyphenyl-1,5-benzothiazepine-4(5H)-one hydrochloride was obtained. mp 211-213℃ [α] ²⁰ _D = +118.0゜ (c = 1.0 water) IRcm ^-1 : 2400 (-N + H), 1740 (ester), 1680
(amide), 1605 (benzene ring) NMRδ ^CDCl3 _TMS : 1.85 (3H, s, COCH ₃ ), 2.86 (6H,
s, N(CH ₃ ) ₂ ), 3.76 (3H, s, OCH ₃ ), 4.95,
5.11 (1H, d, C ₂ -H, 1H, d, C ₃ -H) Example 15 (+)-Erythro-N-(β-dimethylaminoethyl)-2-hydroxy-3-(p-methoxyph) A mixture of 4.53 g of enyl)-3-(o-bromphenylthio)-propionic acid amide, 1.32 g of 93% acetic anhydride, and 45 ml of chlorobenzene was stirred at 70 to 80°C for 1 hour. Add 3.32g of powdered anhydrous potassium carbonate and mix at the same temperature.
Stir for hours. Next, 2.76g of powdered anhydrous potassium carbonate,
38 mg of cuprous iodide was added and the mixture was refluxed for 4 hours in a nitrogen atmosphere to remove by-produced water. After filtering off insoluble matter and washing with water,
Extracted twice with diluted hydrochloric acid. Wash the aqueous layer with ether,
Ethyl acetate was newly added and the mixture was made slightly alkaline with sodium bicarbonate under ice water. The organic layer was separated, washed with water, dried, concentrated under reduced pressure, and converted into a hydrochloride in ethanol.
Filter the crystals, recrystallize with ethanol and (+)-
3-acetoxy-cis-2,3-dihydro-5-
(β-dimethylaminoethyl)-2-(p-methoxyphenyl)-1,5-benzothiazepine-4
2.58 g (57.2% yield) of (5H)-one hydrochloride was obtained. mp 211-212°C [α] ²⁰ _D = +118.5° (c = 1.0 water) IR and NMR were completely consistent with Example 14. Example 16 In Example 15, (+)-erythro-N-(β-
dimethylaminoethyl)-2-hydroxy-3-
(-)- instead of (p-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid amide
Erythro-N-(β-dimethylaminoethyl)-2
-Hydroxy-3-(p-methoxyphenyl)-3
A similar reaction was carried out using 4.53 g of -(o-bromphenylthio)-propionic acid amide. Recrystallized from ethanol to give (-)-3-acetoxy-cis-2,
3-dihydro-5-(β-dimethylaminoethyl)
-2-(p-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one hydrochloride 2.60 g (yield
57.6%). mp 211-212℃ [α] ²⁰ _D = -118.4゜ (c = 1.0 water) IRcm ^-1 : 2400 (-N + H), 1740 (ester), 1680
(amide), 1605 (benzene ring) NMRδ ^CDCl3 _TMS : 1.85 (3H, s, COCH ₃ ), 2.86 (6H,
s, N(CH ₃ ) ₂ ), 3.76 (3H, s, OCH ₃ ), 4.95,
5.11 (1H, d, C ₂ -H, 1H, d, C ₃ -H)

Claims (1)

[Claims] 1 formula [In the formula, X represents a halogen atom, and R represents a lower alkyl group. ] The optically active erythro-type compound represented by N,
By reacting N-dimethylethylenediamine, the formula [In the formula, X is the same as above] An optically active erythro-type amide compound represented by the formula [In the formula, X is the same as above] An optically active erythro-type amide compound represented by the following is obtained, and the resulting acetylated optically active erythro-type amidide is subjected to a ring-closing reaction in the presence of copper powder or a copper compound and a base. formula 1. A method for producing an optically active benzothiazepine derivative, which comprises obtaining an optically active cis-benzothiazepine derivative represented by: