JPS58116476A - Novel preparation of benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a vasodilator for coronary blood vassel through a novel substance, by acetylating a 2-(4-hydroxyphenyl)-3- hydroxy-benzothiazepine derivative corresponding to the desired compound, followed by alkylation. CONSTITUTION:A compound shown by the formual II is acetylated with acetic anhydride, glacial acetic acid, or acetl hydride in the absence of a solvent or in a basic solvent such as pyridine, trialkylamine, etc., to give a novel substance shown by the formula II. It is reacted with a dialkyl sulfate in the presence of an alkali to give a compound shown by the formulaI(R is alkyl, preferably 1-6C, especially methyl or ethyl) in high yield, having vasodilating action on coronary blood vessel and neurotropic action, useful as a remedy for angina of effort, breast pang in old myocardial infarction, etc. This method can be carried out by simple operations, and the alkylating agent is obtainable easily and inexpensively, so it is industrially advantageous.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-(
4-alkoxyphenyl)-3-acetoxy-5-(2
-dimethylaminoethyl)-cis (or trans)-
2,3-dihydro-1,5-benzothiazepine-4 (5
H)-one manufacturing method.

The compound of formula (1) has coronary blood dilating action and psychotropic neuroactive action, particularly d-2-(4-methoxyphenyl)-3-
Acetoxy-5-(2-dimethylaminoethyl)-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-ON is known as an effective therapeutic agent for improving exertional angina pectoris and angina pectoris caused by old myocardial infarction.

The present invention provides 2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-2,3-
Dihydro-1,5-benzothiazepine-4(5]1)-
On (Chew, Pharm, Bull, +26 28
89 (197 g)) as a starting material, the novel compound 2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-1, represented by the formula A new method for synthesizing the compound of formula (1) was completed, which is characterized by obtaining 5-benzothiazepin-4(5H)-one and alkylating this compound.

The method according to the invention is formulated as follows.

(In the above formula, R represents an alkyl group.) Compound (1) is acetylated without 1'! The reaction is carried out using acetic anhydride, glacial acetic acid, acetyl halide, etc. in medium I or a basic solvent such as pyridine or trialkylamine. Alkylation is then carried out by reaction with dialkyl sulfuric acid in the presence of an alkali.

This production method is industrially advantageous because it is easy to operate, the alkylating agent used in the alkylation reaction is easily and inexpensively available, and the reaction is carried out at a high yield.

The alkyl group represented by R1' in the target compound (1) is preferably one having 1 to 6 carbon atoms, such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, secondary butyl, pentyl, impentyl, hexyl.

Examples include isohexyl, among others methyl.

Ethyl is preferred.

Examples of the alkali used in this reaction include sodium hydride, potassium hydride, sodium hydroxide A, potassium hydroxide, and potassium tert-butoxy. As the solvent, tetrahydrofuran, dioxane, acetone, alcohols, or mixed solvents thereof are used, and among them, ether solvents such as tetrahydrofuran and dioxane are preferably used. Give it a turn sometime ξ
These are not limited, and any alkali or solvent that does not interfere with this reaction can be used as appropriate.

In addition, if necessary, if this reaction is performed using an optically active raw material (seal), the optically active target progeny (summer) corresponding to the raw material is l
be moved. Target compounds are, for example, hydrochloride, sulfur I! #Salt, phosphoric acid 1. Inorganic acid salts such as hydrobromide and hydrogen iodide end salts,
Alternatively, commonly used a-addition salts such as organic acid salts such as methanesulfonate, succinate, maleate, malon* salt, and fumarate can be used.

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

Practical example 1 (1) d-2-(4-hydroxyphenyl)-3-
Hydroxy-5-(2-dimethylaminoethyl)-cis-2,3-dihydro-1,5-benzothiazepine-4 (
SM)-ONHO O] was dissolved in acetic acid IGO*/, and 135
Heat and stir at ℃ for 50 hours. After the reaction is completed, acetic acid is pressure-sensitively distilled off 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 in butyl ketone.
~153℃e ta-z-(4-hydroxyphenyl)
-3-acetoxy-5-(2-dimethylaminoethyl)
-cis-2,3-dihydro-1,5-benzothiazepine-4(5H)-one was obtained with optical rotation (a
156.5° (DMFC-〇, 37&) Elemental analysis value (%) C8, H24N204S as field J
m C, 62,99; H, 6,04; N, 7.0
0 Actual value c, 62.83; H, 6, Otori Q; N, 6.8
8 Engineering R Spectrum (KBr 011) 17
42゜1676.1608.1587.151211M
Ii spectrum (CDC” 5-D2U, p p
m) 1.87 (3H, s), 2.32 (611, s)
, 6.00 (ta, a, Jsw7cps) e 6
．． 1g(lHedlJm7(!PIri, 6.56-7.
84 (811, layer) <2) d-2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-cis-2,3-dihydro-1,5-benzothiazepine- 4(5H)-one 7, OF was dissolved in 70 yxl of tetrahydrofuran, 017p of 60% sodium hydride was added while stirring at room temperature, and after stirring for 10 minutes, 2.22 g of dimethyl sulfate was added dropwise. After the dropwise addition, the reaction is completed by stirring at room temperature for about 1 hour.

Add 200tx1 of ethyl acetate to the reaction solution, then add 2x1 water.
After adding 00d and stirring, the acetic acid ethyl ester layer was separated, washed with water, dried (anhydrous with nitric acid), and the fi medium was pressure-sensitively distilled off to obtain an oily d-2-(4-methoxyphenyl)-3-acetoxy- 5-(2-dimethylaminoethyl)-cis-2
,3-dihydro-1゜5-benzothiazepine-4 (5H
)-on 6, F'J the IP. After purifying this product by silica gel column chromatography (Tenma@Moshi: A mixture of chloroform and methyl alcohol 15:1), it is recrystallized from isopropyl ether, with a melting point of 105-106.
Colorless needle-shaped crystals are obtained which exhibit a temperature of .degree.

Elemental analysis value (%) C□I! ,, I, 0.8, theoretical value C, 63,75; 1.6.32; 16.76 actual value C, 63,83; i, 6.34; Ii, 6.72
11 spectrum (MaC17Fk m) 1
742°1671, 1608. 1580. 150
811 [R spectrum (CDCI, PP Otori) 1.87
(3H=!I)-244(6H-s)*3.79(
3H,s).

4.98 (IK, 6. J=7 cps), 5.15
(IH.

(1,7 厘7 CP Lu), 6.86 (2a, a, J 9 apa).

7 , 16-7 , 72 (61 [, m) Optical rotation (g
) Ao-+ 13'3.4 CDMI Cm-03
2> When this product is treated with hydrochloric acid in methyl alcohol by a conventional method, a colorless crystalline powder hydrochloride having a melting point of 210-214°C is obtained.

Elemental analysis value (assault) C, □H116NR04B・llCl
Theoretical value is 0.58.58; JEt6.03;
L6.21 actual measurement value C, 58, 64; ! Its-90
; N, 6.25XR spectrum (KBr ex
) 2915°28! B, 2375. 1740.
1680. 16G0゜1253, 1215.1G
23. 837. 777, v l::/-/k
,, (Li: 236.5 (240GG) optical rotation (g
)2'am+115.8' (H2OC-0,97) Example 2 t-2-<4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-cis-2,3-
Dihydro-1,5-benzothiazepine-4(511)-
After undergoing the same reaction process as tAi,! -2-<
4-methoxyphenyl)-3-acetoxy-5-(2-
dimethylaminoethyl)-cis-2,3-dihydro-1
, 5-benzothiazepine-4(511[)-one hydrochloride is obtained.

Melting point 210-214°C Optical rotation [a)j￥? --116,2@(H,OC-1
,0) Example 3 (1/-2-(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-cis-2,
3-dihydro-1,5-benzothiazepine-4 (5iI
)-one was subjected to the same reaction steps as in Example 1 to obtain each-2-
(4-methoxyphenyl)-3-acetoxy-5-(2
-dimethylaminoethyl)-cis-2,3-dihydro-
1,5-benzothiazepin-4(5H)-one is obtained.

Melting point 135-136℃ Elemental analysis value (%) Cl2I[16'lil o4B
The theoretical value is C, 63, 75; ! 1,6.32;
L6.76 Actual value C, 63,80; H, 6,28
; lr, 6.74 engineering R spectrum (!racl cell m) 1742°1671, 1605. 1580
．． 1508NMR spectrum (CDCI, ppm)
! , 87 (31[.

s), 2.24(Sat s)t 3.79(3
Hs 5) t4.97 (IH, d, J-7ape),
5.15 (IH, d.

JW7 cp@) e6.86 (231, a, 14 c
ps).

7,16-7,73 (6H,m) Example 4 □ d-2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl) obtained in the same manner as in Example 1 -cis-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1.0$' was dissolved in dioxane 5d, and this solution was dissolved in 60% hydrogen and 0.0% sodium chloride.
It is added dropwise to a solution of dioxane 8- dissolved in 1F at room temperature with stirring, and after 5 minutes, 0.315P of dimethyl sulfate is added dropwise while stirring. After the dropwise addition, stirring is continued at room temperature for about 1 hour to complete the reaction. Add 25 parts of ethyl acetate and 25 parts of water to the reaction solution, separate the ethyl acetate layer,
After washing with water and drying (anhydrous sodium sulfate), d-2-(4-
methoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-cis-2,3-dihydro-1,5
-Benzothiazepine-4(SM)-one 0.73F is obtained. Ice crystals are melted at 10 mK in 4 pens, and ξ is dissolved in 5% hydrochloric acid
oTIIt, then made slightly alkaline with 10% sodium hydroxide solution, extracted with 1Gm of 4&benzene, and the benzene layer was separated, washed with water, dried (anhydrous sodium sulfate), and then distilled off to give a colorless substance with a melting point of 105-106°C. becomes needle-like crystals.

Example 5 d-2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-cis-2,3-dihydro-1,5-benzo obtained in the same manner as in Example 1 Thiazepin-4(SH)-one (1.0 F) was dissolved in 3 m of tetrahydrofuran, 4 Llj'E of sodium hydroxide (8 d of tetrahydrofuran) was added, and the mixture was stirred at room temperature for 20 minutes, followed by dropwise addition.

After stirring for 2kS minutes, dimethyl sulfate (0.314F) was added dropwise, and the reaction was completed by stirring at room temperature for about 2 hours. After the reaction, the same operation as in Example 1 was performed, and the melting point ios N
toe℃d-2-(4-/)4/phenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-cis-
2,3-dihydro-1゜5-benzothiazepine-4 (S
0.5 p of colorless needle-like crystals of R)-one are obtained.

Example 6 d7-2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-cis2.
3-dihydro-1,5-benzothiazepine-4 (, 5M
) - on? , 0# was dissolved in 0ml of tetrahydrofuranf and 60'% sodium hydride 0.0% was dissolved while stirring at room temperature.
After adding 7F and stirring for 10 minutes, diethyl sulfate is added dropwise. After the dropwise addition, the temperature was raised to 50°C and stirring was continued for 3 hours to complete the reaction.

When the reactant is treated according to Example 1, its melting point is 1 sis.
dt-2-(4-ethoxyphenyl) exhibiting ~154°C
-3-acetoxy-5-(2-dimethylaminoethyl)
Unoccupied needle crystals of -cis-2,3-dihydro-1,5-benzothiazepin-4(511)-one are obtained.

Elemental analysis value (duck) Cii! 3H211'2048
as theory platform c, 64, 47; H, 6, 59; N
, 6.54 real rs Hama C, 64,51; H, 6,57;
H, 6,52 engineering R spectrum (KBr C1l
) 1742°1670, 1606. 1580.
1505NMR spectrum (CDCI, ppm)
1.48 (3ii*t+ J!7 (!p!I)9 1
．． 96 (31 [15) C2, 35 (6H, s), 4.1
3 (2H, q, J = 7 cps).

5.08 (IH, d, Jm7cpa), 5.25 (
III, d.

Jw7cps)e 6.9t4.00(2H,4*Jm
9cps) C7,08-7.84 (6H, Otori) Example 7 (1) -(4-hydroxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-trans-2
,3-dihydro-1,5-benzothiazepine-4 (5g
)-on 15F to acetic acid 240s? Dissolve IC, 135C
Heat and stir at ss. After the reaction, acetic acid was distilled off under reduced pressure to give df-2-(4-hydroxyphenyl)-3-1cetoxy-5-(2-dimethylaminoethyl)-trans-2,3-dihydro-1,S-benzothiazepine. -4C
A crystalline ILIF of 5B)-one is obtained. When crystals are recrystallized with ethyl alcohol, they become crystals with a melting point of 102 to 103°C.

Elemental analysis value (%) Theoretical value as 01□-, x, o4s
C,62,III f[C6,04; M,7. OO actual value Ce6L93; II, 6.03; 16.90
Engineering R spectrum (KBr Ql) 1743
゜1650, 160J1. 1580. 1510I
Mm spectrum (CDCI3PP) 1.90 (3
H,s).

2.2.8 (6H, s), 4.37 (1M, d, J=1
1 ape), 5.01 (IH, d, JmllOP8)-
6,72 (2H, d, JmlOcps), 6.98 (2
11,6°J-10ape), 7. Hr-7,84(4
11,tm) (2) df-2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-trans-2,3-dihydro-1,5-benzothiazepine-4(5H )-one is methylated in the same reaction step as in column 1 to form df-one, which has a melting point of 67-68°C.
2-(4-methoxyphenyl)-3-acetoxy-5-
(2-Dimethylaminoethyl)-trans-2,3-dihydro-t,S-benzothiazepine-4(51-one) is obtained.

Elemental analysis value (%) 02□H,, N, 0.8 and V theoretical value C, 63,75; H, 6,32; ! f, 6.
76 actual measurement C, 63, 88; H*6.29;
6.74 IRX' (NaC17 Cal
) 174L167G, 1605. 1578
．． 1508NMR spectrum (CDC1a PPI
I) 1.91 (311°8L 2.23 (6H*
s) + 3.76 (3Ht a) C4,53 (IH,
d, J-11 cps), 5.07 (II.

d, Js+wllcps)t 6.77(2H,d,
J-9cpe) C7,02 (2H, d, J-9aps)
, 7.16-J7.64 (41, m).

Claims (1)

[Claims] 2-(4-hydroxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2 obtained by acetylating (5H)-one and expressed as h3 ,3-
Dihydro-1,5-benzothiazepine-4(Sit)-
2 with the formula (wherein R represents an alkyl group)
-(4-alkoxyphenyl)-3-acetoxy-5-
(2-dimethylaminoethyl)-cis (or trans)-2,3-dihydro-1,5-benzothiazepine-4
(SR)-on's mourning) death