JPS59101498A - Novel borane derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:dl-cis-2-( 4-Methoxyphenyl )-3-acetoxy-5-[ N, N-dimethyl-borane (B-N)-aminoalkyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one of formula I (n is 1-5). USE:Synthetic intermediate of ganglion blocking agent, blood platelet coagulation inhibitor, antibacterial agent, carcinostatic agent, and coronary vessel dilator. PROCESS:The compound of formula I can be prepared by reacting 2-(4-methoxyphenyl )-5-dimethylaminoalkyl-2,3-dihydro-1,5-benzothiazepin-3,4( 5H )-dione ( acid addition salt) successively with a borohydride compound and acetic anhydride. The compound of formula II used as a starting material is also a novel compound and is obtained by reacting 2-(4-methoxyphenylmethylidene)-4-dimethylaminoalkyl-2H-1,4-benzothiazi n-3(4H)-one with trimethyl halogenosilane, hydrogen peroxide and water.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel borane rust conductor, dt-cis-2-(4-methoxyphenylene/L
/)-3-a7toxy5-[N,N-dimethyl-poran(B-N)aminoalkyl]-2,3-dihydro-
This invention relates to 1,5-benzothiazepin-4(5H)-one and its production method.

The novel compound (I) of the present invention is a benzothiazepine-type borane compound that was completely unknown as a conventional poran derivative, and has low toxicity and excellent physiological effects such as ganglion blocking effect, platelet aggregation inhibiting effect, and antibacterial effect. Alternatively, it has anticancer effects and is useful as a medicine.

In addition, the novel compound (I) of the present invention is d-cis-2-(4-methoxypheni)v, which is known as a coronary vasodilator.
) -3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-
It is also a useful compound as an intermediate for the synthesis of 4(5H)-one.

The novel borane compound (I) of the present invention can be obtained, for example, by the following synthetic route.

(n represents an integer from 1 to 5) That is, 2-(4-methoxyphenylated)-5-dimethylaminoalktv-2,3-dihydro-1,5-benzothiazepine-3,4(5H)- When dione (II) or its acid addition salt is reacted with a borohydride compound and then with acetic anhydride, the desired borane compound (I) can be easily obtained in high yield. Also, dt-cis-2-(4-methoxypheni/I/)-3-hydroxy-5-[N,
N-dimethyl-porane (B-N) aminoalkyl, 11
-2,. 3-dihydro-1,5-benzothiazepine-
The desired borane compound (I) can also be obtained in high yield by reacting 4(5H)-one (III) with acetic anhydride.

The reaction is generally carried out in the presence of dimethylformamide, diglyme, dimethoxyethane, tetrahydrofuran, dioxane, or if necessary methyl ethyl ketone or methyl isobutyl ketone, in the presence or absence of a small amount of water, at room temperature or with heating for several tens of minutes. She is raped for dozens of hours.

Examples of the borohydride compound used in the reaction include sodium borohydride, potassium borohydride, lithium borohydride, etc., and usually, for example, 1.2 to 2 moles per 1 mole of the raw material (■). .0 mol is preferably used. The reaction can also be carried out in the presence of lithium bromide, lithium iodide, lithium chloride, sodium iodide, potassium iodide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or the like, if necessary.

Post-reaction processing and purification are carried out using conventional methods, such as extraction,
This is carried out by recrystallization, column chromatography, activated carbon treatment, etc.

The novel borane compound of formula (I) thus obtained is a benzothiazepine-based borane compound that has not been known as a conventional borane compound, and is extremely useful as a medicine or an intermediate thereof.

However, the raw materials (TI) and (III) used in the present invention are also new substances, and the raw material (II) is, for example, a known substance 2-(4-methoxyphenylmethylidene)-4- represented by the following formula (IV). dimethylaminoalkyl-2H-1,4-
Benzothiazin-3(4H)-one CJobn K
rapcho and Chester F,T
urk, ,T.

Med-Chem-, l6, 776 (197'a
)] can be easily obtained in high yield by a novel ring expansion reaction in which trimethylhalogenosilane, hydrogen peroxide, and water are reacted. Raw material (][) can be easily obtained by reducing raw material (II) with a borohydride compound.

(n represents an integer from 1 to 5) Next, the present invention will be explained in detail with reference to Examples.

Example 1 2-(4-methoxyphenyl)-5-(2-dimethy)
Aminoethyl/l/)-2,3-dihydro-1,5-benzothiazine-a,+(5H)-dione hydrochloride 5f containing 0.44 ml of water in dimethyl yJ=/remamide 1
Add 2 ml of sodium borohydride and add 0.0 ml of sodium borohydride in a nitrogen gas stream with water cooling and stirring. Gradually add '18f. After the addition, after stirring for 1 hour at an internal fML of 26 to 30°C, 6.27' of acetic anhydride was added. The reaction is completed by stirring for 2 hours at an internal temperature of 50 to 60°C. The reaction solvent was concentrated under reduced pressure, and 60 ml of water was added to the residue.
Extract with 1 wl. The chloroform layer was washed with 20w1 of a 1096 hydrochloric acid aqueous solution, then water, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. When 20 ml of methanol/L was added to the residue and the precipitated crystals were collected, di-cis-2-(4-methoxyphenyl)-3- had a melting point of 186-190°%.
Acetoxy-5-[N,N-dimethyl-borane (B
-N) aminoethyl) -2,3-dihydro-1,5-
Colorless crystals of benzothiazepine-4(5H)-one 8.2
Get an F.

Elemental analysis value (%) Theoretical value as C22H29N204SB C, 61,69; H, 6,82; N, 6.
54 actual measurement value C, 61,72 薯H, 6,87; N
, 6.72 ■, R, spectrum: (Nujol, 3
) 2365°2275.1745,1680,1
610, 1580, 1510°N, Il, R, spectrum yv: (CDC], jppm) 1.89 (s
.

3H), 2.65 (s, 3H), 2.71 (s, 3H)
, 2.80-8.37 (m, 2H), 8.81 (s, 3
H), 4.11-4.72 (m.

2H), 5.03 (d, J=7cps, IH), 5.1
6 (d, J=7cp8.IH), 6.87-7.78 (
m, 8H).

Example 2゜2-(4-methoxyphenyl/)-5-(2-dimethylaminoethyl/1/)-2,3-dihydro-1,5-
To a mixture of 12 ml of dimethylformamide containing 10 g of benzothiazepine-,3,4(5H)-dione hydrochloride and 0.88 ml of water was added 1 ml of sodium borohydride to 10 fft of dimethylformamide under water cooling and stirring in a nitrogen gas stream. A solution containing .55N is added dropwise. After dropping, stir for 1 hour at an internal temperature of 25°C, add 15 ml of acetone, and stir for 1 hour.
After stirring for an hour, acetic anhydride (12.5F) was added and the internal temperature was 5.
After stirring at 0°C for 30 minutes, the mixture was left at room temperature overnight. After adding 70 yt of water to the reaction solution, chloroform'lO*l
Extract with Chloroform extract is 796 hydrochloric acid aqueous solution 40+/! After washing with water, drying with anhydrous sodium sulfate, and evaporating under reduced pressure.

When 50 tttl of methano-IV was added to the residue and the precipitated crystals were collected, dt-IV had a melting point of 185-190°C.
Cis-2-(4-methoxyphenol)-3-acetoxy-5-[N,N-dimethyl-bofun(B-N)aminoethyl)-2,3-dihydro-1,5-benzothiazepine-4(5H 7.5 g of colorless crystals of )-one are obtained.

Example 8 dt-cis-2-(4-
Metkinphenizlz ) -3-hydroxy-5-[
N,N-dimethyl-borane (B-IJ) aminoethyl)-2,3-dihydro-1,5-benzothiazepine-
4(5LT)-one 2y and acetic anhydride 10FI were added, and after stirring at an internal temperature of 50°C for 20 minutes, the mixture was left at room temperature overnight, the reaction solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. After washing with about 7% aqueous hydrochloric acid solution, it is washed with water, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. Methanol/L/ in the residue
When 10 xi is added and the precipitated crystals are taken off, the melting point is 18.
4-18 dt-contains 2-(4-methoxyphenylene/di)-3-acetoxy-5-(N,N-dimethy/revolane (B-N) aminoethyl)-2,3-dihydro-15- Colorless crystals of benzothiazepin-4(5H)-one were obtained at 1°7.

Example 4 Di-cis-2-(4-methoxyphenylene/L/)-3-hydroxy-5-('N, 1
Di-dimethyl m borane (B-N) aminoethyl]-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-one 3 da and 4 f/acetic anhydride were added, and the mixture was stirred at an internal temperature of 50°C for 1 hour, and then left overnight at room temperature. 40tt ice water
After adding tl, extract with chloro 7I/rem 40g/. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. Methanol/L/10 trt in the residue
When the precipitated crystals are collected by adding l, the melting point is 184~1
di-cis-2-(4-methoxyphenylene/di)-3-acetoxy-5-(N.

N-dimethyl-borane (B-N) aminoethyl]-2
,3-dihydro-1,5-benzothiazepine-4 (
2.81 colorless crystals of 5H)-one are obtained.

Example 5.

2-(4-methoxyphenyl)-5-(2-dimethymu-aminoethyl/L/)-2, 3-dihydro-1,
5-benzothiazepine-3,4 (5H)-
8tttl of dimethylformamide to 4g of dione hydrochloride
, methyl ethyl ketone 4 and water 0. 3 5 ml
A solution of 0.621 sodium borohydride dissolved in 4 ttrl of dimethylformamide is added dropwise to the solution in which 0.621 sodium borohydride is dissolved in 4 ttrl of dimethylformamide in a nitrogen gas stream while cooling with water and stirring. Internal temperature after dropping 20
After stirring at ℃ for 1 hour, 4 Mt of acetone was added, and after stirring at the same temperature for 1 hour, 5 g of acetic anhydride was added, and 1 kg of acetone was added.
The reaction is completed after stirring at 50-60°C for 2 hours. After cooling, add 50vtt of water and 50tt of chloroform,
The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. Methanol/l/20 in the residue
ml and the precipitated crystals are collected, the melting point is 183 ~
dl-cis-2-(4-methoxypheni/I/)-3-7setoxy5-CN,,N showing 188°C
-dimethyl-borane (B-N)aminoethyl)-2.3
-dihydro-1,5-benzothiazepine-4(5H)-
2.7 g of colorless crystals of On are obtained.

Example 6, dimethylformamide 5tttt and methyl ethyl ketone 2. 5 Add dl-cis-2-(4
-methoxyphenitv) -3-hydroxy-5
- [BT, N-dimethiμm poran (B-N) aminoethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 2f is added and dissolved by heating briefly. . After cooling, 0.861 g of potassium carbonate and 2.449 g of acetic anhydride were added, and the mixture was stirred at room temperature for 8:11 hours. When washed with
Acetoxy-5-[1 size, N-dimethyl-borane (B-
N) aminoethyl)-2,3-dihydro-1,5-
Benzothiazepine-4 (5°■)-, 1 colorless powder 1
．． Get 9F.

Example 7.

1,47 2-(4-methoxypheny/I/)-5-(
2-Dimethyl-l-reaminoethyl A/)-2, 3-dihydro-1,5-benzothiazepine-3.4(5H)-dione was dissolved in 14 J of dry tetrahydrofuran and diluted with 0.
6y of anhydrous lithium iodide and 0.21% of sodium borohydride were added and stirred under heating under reflux for 3 hours.
421 of acetic anhydride was added, and the mixture was stirred at the same temperature for 1 hour and then allowed to stand overnight. The solvent was distilled off under reduced pressure, and methyl isobutyl ketone and then dilute hydrochloric acid were added to the residue to make it weakly acidic and the mixture was separated into layers.

After washing the organic layer with water, the organic layer was concentrated under reduced pressure to obtain a crystalline solid of 1.41%. By purifying this product from methyl isobutyl ketone, di
-cis-2-(4-methoxypheni)V) -3-acetoxy-5-CN, N-dimethyl-porane (B-N)
0.641 of a colorless powder of aminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.

Example 8 2-(4-methoxyphenyl)-5-C3-dimethylaminopropyl)-2,3-dihydro-1,5-benzothiazepine-3,4(5H)-dione hydrochloride 4.2 tI
dimethylformamide'Iyst and water 0.36
Sodium borohydride dissolved in 4 ml of dimethylformamide in a nitrogen gas stream under water-cooling and stirring was added.
．． 64F solution is added dropwise.

After dropping and stirring at room temperature for 1 hour, 6tttt of acetone was added and stirred at the same temperature for 1 hour, followed by 4. Add 'lf and stir at internal fm 50°C for 1 hour. □After cooling, add 3 water
After adding 5 tnl, extract with 35 trtt of chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. The residue was recrystallized from ethanol to give di-cis-2-(4-methoxyphenylene/I/)-, which had a melting point of 139-i41'C. 2.9y of colorless crystals of 3-acetoxy-5-[N,N-dimethyl-borane (B-N)aminopropyl]-2,3-dihydro-1j5-benzothiazepin-4(5H)-one are obtained.

Elemental Analysis 11 Education (%) C23H31N2048 B
Theoretical value c, 62.44B H, 7,06;
N, 6.33 actual value C, 62,37i) 1,6
．． 98; N, 6.381, R, Spect/L/:
(Nu,)ol,Cm) 2350.1723
.

1678°N, M, R, Spect#: (CDCl3.pp
m) 1.84 (s.

3H), 2.43 (s, 6H), 8.79 (s, 3H)
, 5.04 (d.

J=8cps, H(), 5. '12 (d, J=8cpe
, IH).

6.88-7.80 (m, 8H)-antinicotinic effect The isolated guinea pig ileum was suspended in a Magnus bath filled with Tyrode's solution (30°C). A sample with a fixed concentration was pretreated for 2 minutes, and then nicotine was cumulatively exposed for 1 minute and 30 seconds.
i, and the contraction height of the intestinal tract was drawn on the kymography. The contraction height with 5×10 f/ml nicotine alone was taken as 100%, and the contraction height at each dose of nicotine was expressed as a percentage. 10 Anti-Nicotine Effect Next, the 50% contraction inhibitory concentration (EC5o) of the sample (pretreated for 2 minutes) against guinea pig ileal contraction induced with 5×10 f/ynl of nicotine was calculated.

Anticancer effect: 6 CDFs per group, tumor-bearing mice (p388゜106c
sample (400'l/k
g/day) (days 1 and 5).

intraperitoneally), and the ratio (T/C%) of the survival days of the treated group to the survival days of the untreated group was calculated.

Acute toxicity 1 group of 6 dd-Y male mice (body weight 30-35 g)
The sample was administered intraperitoneally (to 10tttt/kg), and 7
Mortality counts were calculated over a 2 hour period.

As a result, both the compounds of Example 1 and Example 8 had 900
Even when the dose was increased to 1B4/kl, only weak tremor was observed, normal recovery was observed, and no death was observed.

Acute toxicity (number of deaths) Applicant Hamari Pharmaceutical Co., Ltd.

Claims (1)

[Claims] (n represents an integer from 1 to 5)
/)-3-acetoxy-5-[N,N-dimethyl-borane (B-N) aminoalkylcy2. ．． 3-dihydro-
1,5-benzothiazepin-4(5H)-one. (n represents an integer from 1 to 5) 2-(4-methoxyphenylene/l/) -5-
A formula characterized by sequentially reacting dimethylaminoalkyl-1,5-benzothiazepine-3.4(5H)-dione or an acid addition salt thereof with a borohydride compound and acetic anhydride (n is an integer from 1 to 5). di-cis-2-(4-methoxyphenyA/
)-3-acetoxy-5-CN,N-dimethyl-poran(B-N)aminoalkyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. di-cis-2-(4-methoxyphenylene/L) represented by formula 3 (n represents an integer from 1 to 5)
')-3-hydroxy-5-CN, N-dimethyl-borane (B-N) aminoalkyl μ:)-2,3-dihydro-
dl-cis-2-(4- methoxyphenyl)
-3-acetoxy-541H,N-dimethyl m-borane (
B-N)aminoalkyl-2,,3-dihydro-1,
Method for producing 5-benzothiazepin-4(5H)-one.