JPS58113185A - Novel benzothiazepin derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:2-( 4-Hydroxyphenyl )-3-acetoxy-5-( 2-dimethylaminoethyl )-2,3- dihydro-1,3-benzothiazepin-4(5H)-one of formulaI, its optically active isomer, and their acid addition salts. USE:It has coronary vessel dilating activity and is useful as a drug. PROCESS:The compound of formulaIcan be prepared by reacting 2-(4-benzyloxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazopin-4(5H)-one of formula II with dimethylaminoethyl halide, and acetylating the resultant 2-(4-benzyloxyphenyl)- 3-hydroxy-5-( 2-dimethylaminoethyl )-2,3-dihydro-1,5-benzothiazepin-4(5H)-one of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel benzthiasevin derivatives of formula (I), namely 2-(4-hydroxyphenyl)-3-
Acetoxy-5-(dimethylaminoethyl)-2,8-
The present invention relates to dihydro-1,5-benzothiacebin-4(5H)-one and a method for producing the same.

(4) Many benzothiacebin derivatives are known to have coronary vasodilatory effects or actions on the central nervous system, and are therefore very interesting compounds as pharmaceuticals.

The present invention discloses a novel compound, 2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiacebin-4 (5H). -on CI) was synthesized, and it was determined that this compound has coronary vasodilator action and is useful as a pharmaceutical.

The compound (I) of the present invention is, for example, the compound (I) of the formula (ITJ's 2-
(4-hydroxyphenyl)-3-hydroxy-5-(
2-Lenothylaminoethyl)-2,3-dihydro-1,
5-Benzothiacebin-4(5H)-o(5)one [Chem, Pharm, Bull, .
26.2889 (1978)], and the acetylation reaction may be carried out, for example, by heating the compound of formula (b) in acidic vinegar.

This reaction method and another method described later! In the synthesis method described above, when an optically active compound of formula (II) in which the 2- and 3-positions are in cis or trans configuration is used, the target compound of formula i) corresponding to each optical activity can be obtained.

The target compound of formula (I) thus obtained can be prepared by a known method of converting the amine into its acid salt, if necessary.
For example, hydrochloride, sulfate, phosphate.

It can be an inorganic acid salt such as bromic acid salt, or an organic acid salt such as methanesulfonate, succinate, maleic acid salt, bleached stone salt, etc.

(6) Compound 16 (■) of the present invention can also be obtained by the following synthetic route (
I) In this production process, firstly, 2-(4-benzyloxyphenyl)-3-hoxy-2,3-dihydro-
1,5-pen, zothiacepine-4(5H) (7) one on 01l) [Chem, Pharm, Bul l
, 2889 (1978)) with dimethylaminoethyl halide. The reaction is generally carried out in the presence of a base.

As bases, alkali metal compounds such as Na!・
Rium methylate!・Rium ethylate.

Propoquine sodium, tert-7 toxin potassium,
Preferably used are alkali metal alcoholades such as tert-oxysodium, hydroxides (hypotassium, hyalkali hydroxides such as mono-arsenium hydroxide, sodium hydride, etc.).Common reaction media include alkylation. It is preferable to use a solvent commonly used in the reaction, such as dimethyl sulfoxide and dimethylformamide.

Examples include toluene, xylene, dioxane, tetrahydrofuran, and alcohols.

By the above reaction, a new compound 2-(4-draw 1
．． 1 of 5-benzothiazepin-4(5H)-one (ff) is obtained.

(8) Next, the compound of formula (IV) is arranged with acetyl to form a new compound, 2-(4-benzyloxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,8
-dihydro-1,5-benzothiazepine-4(5H)-
Obtain ON (V).

Examples of the acetylating agent used in this reaction include acetic anhydride, glacial acetic acid, and acetyl halide. This reaction is carried out without a solvent or in a basic solution/ring such as pyridine or l-realkylamine.

Next, the compound (■) obtained above is depensylated to obtain compound 1Q(I). This reaction is carried out by reacting compound (v) with, for example, a solution of hydrogen bromide in acetic acid.

The compounds CI) thus obtained are useful as medicines, for example coronary vasodilators.

Next, the present invention will be described in detail with reference to implementations and sequences.

Example 1 (1) 60% in dimethyl sulfoxide 120 me
Add 84 f of thorium hydride and stir at 70°C for 1 hour (9). Beat the cold mixture (4-benzyloxyphenyl)-3-hydroxy-cis-2,3-dihydro-1,5-benzothiazepine-4(5)T)-, and 16y at room temperature for 1 hour. Stir. Next, N,N-dimethylaminoethyl chloride 68y was added dropwise over 10 minutes.
Stir at room temperature for 80 minutes, raise to 45℃? f! After stirring for 2 hours, the reaction is complete. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate.

After washing the extract with water and drying with anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure to obtain d-2-(4-hensyloxyphenyl)-3.
-Hydroxy-5-(2-dimethylaminoethyl)-cis-2,3-dihydro-1,5henzothiasebin-4 (
5H)-one crystals 1B, 5y are obtained. When crystals are recrystallized from ethyl alcohol containing a small amount of tetrahydrofuran, colorless crystals with a melting point of 146°C to 147°C are obtained.

Optical rotation [α]D: +210 (DMF, c2o3) Elemental content 1ffilI (L-8) c2a H2B N20
3 S as Rinakago 1' direct C, 69, 62iH, 6
, 29iN, 6.25 actual measurement C, 69, 65iH, 6
, 26-N, 6.24 (10) IR Spectrum KBrm-) 3425, 1665,
1602°1580.1508 NMR spectrum (CDCI B-D20.ppm
) 2.26 (6H, s).

4.26 (H (, d, J-7 cps) 4°88 (18° d, J = 7C113) 5.06 (2H, s), 6.8
4-7.80 (13H, m) +2+ d-2-(4-benzyloxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-cis-2,3-dihydro-1 obtained by t++ , 5-benzothiacebin-4(5H)-one (1) was taken, dissolved in 100 ml of acetic anhydride, and stirred at 90°C for 3 hours. After the reaction, acetic anhydride was distilled off under reduced pressure, and the residue was Dissolved in ethyl acetate, washed with 5% aqueous sodium bicarbonate solution, washed with water, dried over anhydrous sodium sulfate, and then reduced and distilled off the solvent to obtain d-2-(4-benzyloxyphenyl)- 3
-acetoxy・-5-(2-dimethylaminoethyl)-
cis-2,3-dihydro-1,5-benzothiazepine-
10.8y of crystals of 4(5H)-one are obtained. When ice crystals are recrystallized from acetone, they form colorless, clear crystals with a melting point of 133-134°C (11).

Optical rotation r120 = +2.3° (Me OH, C = 0
．． 3)l] Elemental analysis value (%) C2BI ((capital) Theoretical value as N204S C, 68, 55iH, 6, 16iN, 5.71 Real 4IIIl Direct C, 68, 58, H, 6, 18, N, 5
．． 71TR spectrum (KBr ts) 1740
, 1679.160B.

1580.1.509 NMR spectrum (CI) CI3 ppm) 1.88
(3Fl, S).

2.33 (6H, s), 5.00 (LH, d, J=7c
ps), 5.16 (FH, d, J=7 cps).

5.07 (2H, s), 6.72-7.72 (13H.

m) +31 +21 obtained -d-2-(4-benzyloxyphenyl)-3-acetoxy-X)-(2-dimethylaminoethyl)-'/south-,3-dihydro 1,5-
75 ml of acetic acid solution containing hydrogen bromide of penzothiasebin-4(5R)-one 15yylO form! and stir at room temperature for 1 hour. Next, the solvent was distilled off under reduced pressure, water and diisopropyl ether were added to the residue, and after stirring for a while, 11 parts of water was taken out, the pH was adjusted to 8 with diluted ammonium (12) aqueous solution, and the precipitate was extracted with ethyl acetate. ,
After washing the extract with water and drying with anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure to obtain d-2-(4-hydroxyphenyl)-
3-acetoxy-5-(2-dimethylaminoethyl)-
Cis-2,3-jihi! Oily proboscis of 1,5-benzothiazepine-4(5H)-one 11. Oy is obtained. When ice crystals are recrystallized with methyl isobutyl ketone, their melting point is 1.
51 ~ Elemental analysis (%) Ethics and directness as C21H24N204S C, 62,99; H, 6, 04; N, 7.
00 actual measurement-rti C, 62, 9B, H, 6, 0? , N
, 6.98■R spectrum (KBrm) 1742,
1676°1608.1587.1512 NMR spectrum (CDCI3-D20.ppm)1.
87 (8H.

s) 2.32 (6H, s) 5.00 (IH, d.

J = 7 cps, ) 5.18 (IH, d, J near cps
) 6.56-7.84 (8H, m) Fu; Ike) Kari 2 (13) d-2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-cis2. 3-
Dihydro-1,5-benzothiacebin-4(5H)-one lOy was dissolved in 100 d of acetic acid and incubated at 115 °C for 50 min.
Heat and stir for an hour. After reaction route r, acetic acid is distilled off under reduced pressure to obtain a 9.8y oil. This product was purified by silica gel column chromatography (developing solvent: 15:1 mixture of chloroform and methyl alcohol), and then recrystallized with methyl isobutyl ketone, resulting in a melting point of 151-153°C.
Shows d-2(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-cis-2,
3-dihydro-1,5-benzothiacebin is obtained.

Example 3 i'-2-(4-hydroxyphenyl)-3-acetoquine-i:+-(2-dimethylaminoethyl)-cis-2,3-dihydro-1,5-benzothia ζvin-4(5
H)-one can be obtained by the same reaction as in Example 1ylJl or 2.

(14) Melting point 151-153°C Optical rotation [α] −1.55.6° (1) MF C
=0.285) Original analysis area (%) C21H24N2
Theoretical value as O4S C, 62,99; H, 6,04;
N, 7.00 Experiment C, 62,94iH, 6,05i
N, 6.97 Example 4 dNo2-(4-hydroxyphenyl)-3-acedoxy5-(2-dimethylaminoethyl)-ras-2,3
-dihydro-1,5-benzothiazepine-4(5H)-
On is obtained by the same reaction as in Example 1 or 2.

Melting point 195-196℃ Elemental analysis value (%) Theoretical value as C21H24N204S C, 62,99; H, 6,04; N, 7.00 Actual measurement c, 6.2.95; H, 6,07,; N ,6.
95 Example 5 +++ Dimethyl sulfoxide 9 60% to Q me
Add sodium hydride i, a2y 11, 65-70
Stir for 1 hour at °C. Cold-soaked di-2-(4-benzyloxyphenyl)-3-hydroxy-trans-2(1
5), 3-dihydro-1,5-benzthiacebin-4 (5H
)-one (11.39 g) was added and stirred at room temperature for 1 hour. Next, add 10% of N,N-dimethylaminoethyl chloride 484y.
After stirring at room temperature for 30 minutes, the reaction was completed by raising the temperature to 45°C and stirring for an additional 2 hours. After cooling, the reaction product was poured into water and a small amount of ethyl acetate was added, stirred for a while, and the precipitated crystals were collected by filtration, washed with water, and dried to give dl.
-2-(4-benzyloxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-1-lance-
2,3-dihydro-1,5-benzthiacebin-4 (5
Crystals of H)-one 11. ! M' is obtained.

Ice crystals have a melting point of 163-164 when recrystallized from ethanol.
Obtain colorless crystals showing ℃.

Elemental analysis: Direct C%) As C26HVBN203S, 9 turtles (Direct C, 69, 62; H, 6, 29; N
, 6.25503 NMR spectrum (CDCI 3 ppm)
2.23 (6H, s) (16) 4.18 (2H, s), 502 (2H, s) 6.6 (1
-7,72(18H,m) (2+ [+1)
0Ile, cooled to 0-5°C and added salt f with stirring.
Hyacetyl 2y was added dropwise over 10 minutes, and the reaction was completed by stirring for 5 hours under cooling. Pour the reaction mixture into ice water,
After extraction with chloroform, washing the extract with water and drying with anhydrous sodium sulfate, chloroform was distilled off under pressure, resulting in d and e-2.
-(4-hensyloxyphenyl)-3-acetoxy-
5-(2-dimethylaminoethyl)-trans-2,3
-dihydro-1゜5-benzothiazepine-4(5H)-
Obtain 8.72 crystals of on. When ice crystals are recrystallized from ethanol, they become colorless crystals with a melting point of 120-122°C.

Elemental analysis direct C2B H80N204 Theoretical value as S C, 68,55i H, 6,16i N, 5.
71 actual measurement value C, 68, 58iH, 6, 13iN, 5.
78IR spectrum (NaCl cell, n) 1
74B.

1675.1603,1582,151ONMR spectrum (CDCI3 ppm) 1.90 (3H, s
) (17) 2.22 (6H, s) 4.53 (IH, d, J=11c
ps) 5.02 (2H, s) 5.06 (IH, d.

J=11cps)6.76-7.70(13)1. m)
+a dt-2-<4-hensyloxyphenyl)=
3-acetoxy-5-(2-dimethylamineethyl)-
Trans-2,3-dihydro-1,5-penzothiacebin-4(5H)-one 10y is dissolved in 79me acetic acid solution containing 7% hydrogen bromide and stirred at room temperature for 3 hours to complete the reaction. Next, the solvent was distilled off under reduced pressure, water and diisopropyl ether were added to the residue, and after stirring for a while,
The aqueous layer was taken out, the pH was adjusted to 8 with diluted aqueous ammonia, the precipitate was extracted with ethyl acetate, the extract was washed with water and dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off under reduced pressure.
4-hydroxyphenyl)-3-acetoxy-5-(2
7.8y of crystals of -dimethylaminoethyl)-trans-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.

When ice crystals are recrystallized with ethyl alcohol, their melting point is 102~1
It becomes a crystal at 03°C.

(18) Elemental analysis: Direct (form) C21N24 N204 Theoretical value as S (・ぢ) C, 62,99〼H, 6,04iN
, 7.00 Actual value (Φ) C, 62,98; H, 6,01
;N, 6.98IR spectrum (KBr, m)■
'14.8,1650°1608.1580,151O NMR spectrum (CDCl2 ppm) 1.90 (
8H, S) 2.28 (6H, s) 4.37 (LH, d,
J-=11 cps) 5.01 (IH, d, J=11 CI
)S)6.72(21(,d,J=10 cps)6.
98 (2H1d, J-10CpS) 7.16-7.84
(4H, +η) Example 6 dj-2-(4-hydroxyphenyl)-3-hytroquine-5-(2-dimethylaminoethyl) = trans-2
,3-dihydro-1,5-peptiazepine-4 (5H
) - Saino 151? Dissolved in acetic acid 240I, le, 13
Stir hot at 5°C for 55 hours.

After the reaction, acetic acid was distilled off under reduced pressure to give d-2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-trans-2°(19) 8-Shihyrot. , 5-henzthiasebinose 4 (
5H)-one crystal 12.2y was obtained. Recrystallization of 16J crystal from ethyl alcohol gave a melting point of 102~1゛0.
4f with the crystal at 3°C.

(20)

Claims (1)

[Claims] 1. 2-(4-hydroxyphenyl)-3-acedoxy-5-(2-dimethylaminoethyl)-2,3- represented by the formula
A novel benzothiacebin derivative consisting of dihydro-1,3-benzothiasebin-4(5H)-one, its optically active forms and acid addition salts thereof. 2. The derivative according to claim 1, wherein in the formula of the preceding paragraph, the 2nd and 3rd positions are in a cis configuration. 3. The derivative according to claim 1, wherein in the formula of claim 1, the 2nd and 3rd positions are arranged in a lance shape. (1) 2-(4-benzyloxyphenyl)-3-
2-(4
-benzyloxyphenyl) = 3-hydroxy-5-(
2-dimethylaminoethyl)-2,3-dihydro-1,
5-Benzothiacebin-4(5H)-one is obtained, and then this is converted into 2-(4-pennyloxyphenyl)=3-acetoxy-5-(2-dimethylamineethyl)-2,8-dihydro represented by a. -1,5-benzothiazepine-4
(5H)-one is obtained, which is then translated into 2-(
4-hydroxyphenyl)-3-acetoxy-5-(2
-dimethylaminoethyl)-2,3-dihydro-1,5
- A method for producing benzthiacebin-4(5H)-one or an acid beaten salt thereof. 2-(4-hydroxyphenyl)-3-hyI represented by
Chroxy-5-(2-dimethylaminoethyl) (3) -2,3-Novidro-1,5-benzothiasebin 4 (
2 characterized by acetylating the 5H)-one
-(4-hydroxyphenyl)-3-acedoxy2.
3-dihydro-1,5-benzothiacebin-4 (5H)
A method for producing -one or its acid N salt.