JPS58118578A - 2-(4-acetoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3- dihydro-1,5-benzothiazepine-4(5h)-one and its preparation - Google Patents

Abstract

NEW MATERIAL:2-(4-Acetoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-di hydro-1,5-benzothiazepine-4(5H)-one shown by the formulaI, its optical active substance, or its acid addition salt. USE:A drug having coronary blood vasodilating action and action on central nervous system. PROCESS:A compound shown by the formula II is acetylated to give a compound shown by the formulaIor its acid addition salt. Or, a compound shown by the formula III is reacted with an amino ethyl halide to give a compound shown by the formula IV, which is acetylated to give a compound shown by the formula V. This compound is debenzylated to give a compound shown by the formula VI, which is acetylated to give the compound shown by the formulaIor its acid addition salt.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel benzothiazepine derivatives, 2-(4-acetoxyphenyl)-3-acetoxy-
The present invention relates to 5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(511)-one and a method for producing the same.

Among benzothiazepine conductors, many compounds are known to have d vasodilatory effects and effects on the central nervous system, and 1!
! It is a very interesting compound as a drug.

The novel target compound of the present invention 2-(4-acetoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-4
(5H)-one (1) is, for example, 2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-2,3-
Dihydro-1,5-benzothiazepin-4(51)-one (Chew, Pharm, Bull.

26.2889 (197g)).

This acetylation reaction involves the compound of formula (1) and butyric anhydride,
The reaction is carried out with an acetylating agent such as hydroacetic acid or acetyl halide without a solvent or in a basic amine solvent such as pyridine or trialkylamine.

If an optically active compound of the formula (Circle) in the 2.3-position cis or trans form is used in this reaction, the target compound of the formula (Natsu) corresponding to the respective optical activity can be obtained.

These compounds are hydrochlorides, sulfates, and phosphates.

Unbridged acid salts such as nitric acid and salts, or methanesulfonate salts,
Contains Kohakuura salt, maleate, malonate, etc. 4! Ti
w1tn.

The novel compound (1) of the present invention can also be synthesized by the following synthetic route.

(1) (Y) (In the formula, X represents a halogen atom.) That is, 2-(4-benzyloxyphenyl)-3-
Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (1) (Chgm, Pha
rm, Bull, , 2L 2 g 89 (1
978)) and dimethylaminoethyl halide in the presence of an alkali metal salt to form a novel compound 2.
-(4-benzyloxyphenyl)-3-hydroxy-
5-(2-dimethylaminoethyl)-2,3-dihydro-1,s-benzothiazepin-4(5H)-one (ff
).

The compound of formula (ff) is acetylated to produce a new compound, 2-(4-benzyloxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothia. Zepin-4(5H)-one (
V) is obtained. Then, when the compound of formula (l) is reacted in a bromide acetic acid solution, 2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)=2,3-dihydro of formula 1) is obtained. -1,5-benzothiazepin-4(5H)-one is obtained. By acetylating the compound of this formula (V), we obtain the target compound 2-(4-
Acetoxyphenyl group 3-acetoxy-5-(2-dimethylaminoethyl)-2°3-dihydro-1,5-benzothiazepin-4(5H)-one (1) is obtained.

Examples of the alkali metal salts used in this case include sodium methylate, sodium ethylate, sodium propoxy, potassium tert-butoxy, sodium tert-butoxy, sodium hydride, potassium hydroxide, and sodium hydroxide. Examples of the #I medium used include dimethyl sulfoxide, dimethylformamide, toluene, xylene, dioxane, tetrahydrofuran, alcohols, and other bath media used in the perturbation alkyl 1tS reaction. Furthermore, as an acetylating agent used in the acetylation reaction, Yosuisuiura.

Examples include glacial acetic acid and acetyl halide. This acetylation reaction is carried out without solvent or in a basic solvent such as pyridine or trialkylamine.

Next, the present invention will be explained in detail with reference to Examples.

Example 1 (I) 1z Hydroxylic Acid 15+w/1cd-2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-cis-2,3-dihydro-hydrohydrochloric acid.

5-benzothiazepine-4(5M)-one2. Add Of and heat to reflux for 4 minutes. After the reaction, the solvent was distilled off under reduced pressure, and f
Chloroform and water were added to the lJ product, and the mixture was made slightly alkaline with a 5% aqueous sodium hydroxide solution.The chloroform l- was separated, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a curved shape. d-2-(4-acetoxyphenyl)
-3-acetoxy-5-(2-dimethylaminoethyl)
-cis-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 2.4 years old. When the crystal is recrystallized using diisopropyl ether and methanol, a crystal with a melting point of 58 to 60°C is obtained.

Original search analysis calm (%) C23"2605NIS as theory 1111 C,62,43; H,5,92; H
,6,33 big Ik! I plate C, 62, 29; Hw5.
85; N, 6.371 Engineering R spectrum (NaC17”) 293G
.

2850.2815,2760,1750,1675°1600.1580.1505.1470.1440°1405°NMR spectrum (CDCl3 PPn1) 1
, 88 (3H, s) s 2-29 (9H, s)
+ 5-01 (I H-d-Jsm7cpe),
5.15 (IH, d, J = 7 cps) * 7.03
-7.73 (8H, m) (2) When crystal is converted into a hydrochloride salt in an alcohol solution by a conventional method, a colorless crystalline powder having a melting point of 123 to 126°C is obtained.

Elemental analysis value (%) C2, H260, N25 - Theoretical value as HCI C, 57,62; H, 5,63; N,
5.84 actual island value Ce57-47; fi, 5.54;
N, 5.95 engineering R spectrum (NJLCl cell am
) 2535°2580, 249G, 175
0. 1680. 1610°1585, 1505 MMR spectrum (CDCI, ppm) 1.88
(3H, s), 2.28 (3H, s), 2.87
(6H.

broad a) e 5.03 (1M+ do J Edict 7
cps) w5.12 (IH, d, J-7aps, 6
．． 86-7.74 (8H, m) Optical rotation'-y-'-")" + 116.602 (Hg
OC Cabinet O, 336) Example 2 d-2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-cis-2,3-
8.589 g of dihydro-1,5-benzothiazepin-4(5H)-one was dissolved in 13 l of pyridine, and acetyl chloride 0, ssp was added dropwise while stirring under water cooling.

The reaction is completed by stirring for 4 hours under water cooling after 1 hour. Pressurize into reaction water and extract with chloroform. Chloroform 1 was washed with water, anhydrous and dried over nitric oxide, and then distilled off under reduced pressure to give an oily d-2-(4-acetoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-cis-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
- Obtain 4.3V on.

Real 5IrA3 Real&t%il also $12 and 14411 Lrz-2-(
4-hydroxyphenyl)-3-hydroxy-5-(2
-dimethylaminoethyl)-cis-2,3-dihydro-
1,5-benzothiazepin-4(5H)-one to t-
2-(4-acetoxyphenyl)-3-acetoxy-5
-(2-dimethylaminoethyl)-cis-2,3-dihydro-1,5-benzothiazepin-4(5B)-one is obtained.

Melting point 58-60℃ Elemental analysis 1 (%) 023H260,N2B Theoretical field value C, 62,43; H, 5,92; L6.3
3 Sekikan value C, 62, 57; H, 5, 69; N, 6
．． 36 Optical rotation of genuine hydrochloric acid group [a)”--116,
428 (H, OC-0, 304) Example 4 * d-2-(4-
hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-trans-2,3-dihydro-
1,5-benzothiazepin-4(5H)-one to d-
2-(4-acetoxyphenyl)-3-acetoxy-5
-(2-dimethylaminoethyl)-trans-2,3-
An oily compound of dihydro-1,5-benzothiazepin-4(5H)-one is obtained.

Elemental analysis value (%) C,23Has Oa Na S
Reasonable value C, 62, 43; H2S-92;
N, 6.33 Actual value C, 62,55; ■, 6.08
M, 6.27 Example 5 1u-2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-cis-2,3-dihydro in the same manner as in Example 1 or 2 -1,5-benzothiazepin-4(5H)-one to dt-2-(4
-acetoxyphenyl)-3-acetoxy-5-(2-
dimethylaminoethyl)-cis-2,3-dihydro-1
, 5-benzothiazepin-4(5H)-one is obtained.

1 point 131-133℃ Elemental analysis value (%) C! 3 H2S 01s'2S
The theoretical value c, 62.43; ! 1,5.92;
L6.33 actual measurement ia C, 62,60; H, 5,7
9; H,6,24 Example 6 a-2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-trans-2,3 by the same method as in Example 1 or 2 -dihydro-1
, 5-benzothiazepine-4(5B)-one to #-2
-(4-acetoxyphenyl)-3-acetoxy-5-
(2-dimethylaminoethyl)-trans-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.

Melting point 146-147°C Elemental analysis m<%) Ma value as C23H2S 05'2S C, 62,43; H, 5,92; N, 6
．． 33 Refreshing value c, 62.29; H, 6,12; N
, 6.31 engineering R spectrum (NaCl cell 1 n 1
750゜1675.15g0.1505.1400MM
B spectrum (CDCIs ppm) 1-92
C3H,s), 2.23(611,a)*2.26(3
1,s).

4.54 (IH, d, J=11 cps), 5.03
(IH.

d, J 11 cps), 7.92-8.61 (8H
, Peng) Fruit (Example 7) (1) Add 1.84 F of 60% sodium hydride to 120 g of dimethyl sulfoxide and stir at 70°C for 1 hour. Cold barley d-2-(4-benzyloxyphenyl)-3
-Hydroxy-cis-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 16! Add i and stir at room temperature for 1 hour. Next is N.

6.82% of N-dimethylaminoethyl chloride was crushed over 10 minutes, stirred at room temperature for 30 minutes, then heated to 45°C and further stirred for 2 hours to complete the reaction. Pour the cold barley mixture into ice water and extract with ethyl acetate.

The extract was washed with water, dried over anhydrous sodium sulfate, and ethyl acetate was distilled off to give d-2-(4-benzyloxyphenyl)-
3-hydroxy-5-(2-dimethylaminoethyl)-
Cis-2,3-dihydro-1゜5-benzothiazepine-
4(5H)-one crystal 18.51! get. 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.

, 20 ・l redundancy: degree (αJD−+2.1°(DMF C=0.
3) Elemental analysis +a! (%) 026 H28H2”s
Theoretical value as 8 C, 69, 62; H+6-29
; N, 6.25 actual measurement value C, 69,65; H, 6,
26; N, 6.24IR spectrum (KBr (:
11) 3425°1665, 1602. 1
5JIo, 150811MR spectrum (CDC
I, -D, Oppll) 2.26 (6H, @), 4
．． 26 (IH, d, J proverb 7cps), 4.88 (IH+
dt J-7cps)e 5.06(21,s
), 6.84-7.80 (131 (, ■) (2) (
1) d-2-(4-benzyloxyphenyl)-
3-Hydroxy-5-(2-dimethylaminoethylncis-2,3-dihydro-1,5-benzothiazepine-
Take IOP of 4(5H)-one and add anhydrous vinegar m1oo+s/
and stirred under heating at 90°C for 3 hours. The reacted barley vinegar was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. This was washed with an aqueous solution of sodium bicarbonate, further washed with water, dried with anhydrous nitric oxide, and the lft medium was quenched. ! When you leave,
d-2-(4-penzyloxyphenyl-3-acetoxy-5-(2-dimethylaminoethyl)-cis)2.
3-dihydro-1,5-benzothiazepine-4 (5H)
-on crystal 10.8y is obtained. When quartz is recrystallized from acetone, colorless crystals with a melting point of 13.3 to 134°C are obtained.

0 Optical rotation fK Lrx”)D−+2.3°(MaOHC=
0.3) Elemental analysis value (%) c211H3ON2o4
Theoretical value for s: C, 68,55; H, 6,16
; N, 5.71 actual measurement value C, 68, 58; H, 6,
13; H, 5,711R spectrum (KBr am
) 1746°1679, 1603. 1
580. 1509NMRX vector (CDCI, pp
m) 1.88 (3H, a), 2.33 (6H,
s), 5.00 (IH.

d, J-7 cps) t 5-16 (IHe do
J-7cps)+5.07(2Ls), 6.72
~7.72(13H,III)+3) (d-2-(4-benzyloxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-cis-2 obtained in 2,1
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one 152 is dissolved in 75xl of acid 611 solution containing 10% hydrogen bromide and stirred for 1 hour at Kei-temperature. Next, the solvent was distilled off under reduced pressure, water and diisopropyl ether were added to the residue, and after stirring for a while, 711 parts of water was taken out.
The pH was adjusted to 8 with dilute 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 to yield d-2-(4-hydroxyphenyl)-3-acetoxy. -5-(2-dimethylaminoethyl)-cis-2,3-dihydro-1,5-benzothiazepin-4(511)-one oil 11. OF is obtained. When crystal is recrystallized with methyl isobutyl ketone,
Melting point! Obtain crystals at 51-153°C.

Optical rotation Ca]20-+156. r (pMrC■0
．． 278) Elemental analysis value (vomit) Ca□H, 4) 1,048 as theory - Ce62.99; it6-04; M, 7.
OO actual value Cl62J3; it, 6.07; N,
6J8rRX pect k (KBram)
1742°1676, 160JI, 1587.
15121 Summer R spectrum (CDCI3-D, O
, ppm) 1.87 (3H, *)t 2.32 (6H
,・), S,0O(lu+dl J7cps)
+ 5-18 (IHI dl J 7cps),
6.56-7.84 (8H, m) (4) (3)
d-2-(4-hydroxyphenyl)-3-acetoxy-5-(2-diethylaminoethyl)-cis-2 obtained in
,3-dihydro-1,5-benzothiazepine-4 (5K
)-on 2. Of was added to a mixture of anhydrous vinegar #5m and acetic acid 1G+wl, and heated to reflux at 4 o'clock. After the reaction was completed, the solvent was distilled off under reduced pressure, and the oily residue was dissolved in chloroform.
After washing with a saturated aqueous sodium bicarbonate solution, washing with water, and drying (anhydrous sodium sulfate), the chloroform was distilled off under reduced pressure to give a sticky oil of d-2-(4-acetoxyphenyl)-3-acetoxy-5-(2-diethylaminoethyl). )-cis-2,3
-dihydro-1,5-benzothiazepine-4(5H)-
On 2. Get IP. When crystals are recrystallized from diisopropyl ether and a small amount of methanol, crystals with a melting point of 58 to 60°C are obtained.

Example 8 By a method similar to Example 7, d-2-(4-benzyloxyphenyl)-3-hydroxy-trans-2,3
-dihydro-1,5-benzothiazepine-4(5!trione to d-2-(4-acetoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-trans-2,3- Dihydro-1,5-benzothiazepine-4
(One ounce of oil is obtained per 5 ml.

Elemental analysis value (%) C,, HR, o,, s, s as theoretical value Ce62.43; 5, 5.92; H, 6
, 33 actual value C, 62, 39; it5-9J R,
6,25 engineering R spectrum (Nail cell ffi)
1750°1675.1680.1505.140
0mlli spectrum (CDCI3 ppm)
1.92 (31, s), 2.23 (6H, s), 2
．． 26 (3H.

a), 4.54 (1g, d, J 11 (!P8)
, 5.03 (IH, d, J-11cps), 7.
92-8.61 (8H,!l) Applicant Hama JI! Yakuhin Kogyo Co., Ltd.

Claims (4)

[Claims] 2-(4-acetoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethynolyl 2.3-
Dihydro-1,5-benzothiazepin-4(5H)-one and its optically active substance or its i'+:2rsu〃1
11° (2) A compound of -gW, js 1 , and shellfish according to the present invention, in which the 2nd and 3rd positions of formula (1) are cis forms. (3) The compound according to claim 1, wherein the 2nd and 3rd positions of formula (1) are trans isomers. (4) 2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-2,3-
Dihydro-1,5-benzothiazepin-4(5H)-one is acetylated to produce 2-(4-acetoxyphenyl)-3-acetoxy-5-(2-dimethylaminoe%)-2, Process for producing 3-dihydro-1,5-penzothiazebin-4(5H)-one or its acid addition salt (5
) 2-(4-benzyloxyphenyl)-3- represented by the formula
Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is reacted with dimethylaminoethyl halide to produce 2-(4-benzyloxyphenyl)-3-hydroxy-5 represented by the formula -(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, which is then acetylated to give formula % formula % sevin-4(5H)- 2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethynolyl 2.3-
dihydro-1,5-benzothiazepin-4(5H)-one, which is then acetylated to give 2-(4-acetoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl) of the formula -2,3-
Method for producing dihydro-1,5-benzothiazepin-4(51)-one or its acid addition salt