JPS5829779A - Preparation of n-aminoalkyl-1,5-benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound for coronary vasodilators, etc. safely, by cyclizing an alpha-2-acyloxy-3-(substituted phenyl)-3-(2-aminophenylthio)-propionic acid derivative, and dialkylaminoalkylating the nitrogen atom at the 5-position of the resultant compound. CONSTITUTION:An alpha-2-acyloxy-3-(substituted phenyl)-3-(2-amino-phenylthio)- propinoic acid derivative of formulaI(X1 and X2 are H, halogen, alkyl or alkoxyl; R is alkyl) is reacted with a 1-substituted-2-halopyridinium salt of formula II (X3 is halogen; A<-> is ion of haogen, BF4, p-toluenesulfonic acid, methylsulfuric acid or perchloric acid respectively; Z is alkyl) in the presence of a tertiary amine to give a compound of formula III, which is then reacted with a compound of formula IV (X is halogen; Y is alkylene; R1 and R2 are alkyl) in the presence of a phase transfer catalyst and a base to afford the titled compound of formula V in high yield. USE:Psychotropic and nerve agents.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides N-aminoalkyl-7, which is useful as a pharmaceutical!
- A method for producing benzothiazepine derivatives. ]! Specifically, the present invention relates to the general formula (wherein X and X each independently represent one hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, or a lower alkoxy group;

α-co(substituted phenyl)-3-acyloxy-! represented by R and R1 are lower alkyl groups, and X is an alkylene group). -(N,N-noalinoalkyl)-1, J-J)hydro-1.

S-benzothiazepine-4<(jH)-one derivative (N
-Ainoalkyl! - benzothiazepine derivative).

The above N-annoalkyl l,j-pensothiazene conductor, especially α---(Hiro-methoxy-phenyl)-3-
Acetoxy-t-(-1-dimethylaminoethyl)-2,
3-dihydro-7,j-benzothiazepine-tei (3H)
-on is known to be a useful drug as a coronary vasodilator or psychotropic agent (Special Publication No. 1 I4-jH
(Refer to No. 3RIS).

N-amino-alkyl-l conventionally indicated by general length (I)
, 3-benzothiazepine derivatives, such as -1(termethoxyphenyl)-3-acetyloxy-! -(Codimethylannnoethyl)-1,3-dihydro/,j-benzothiazepin-41(jH)-one is co(termethoxyphenyl)-3-acetyloxy-co3-dihydro-7,S- Benzothiazepine! (!rH)-one was prepared by treating sodium monohydride with dimethyl sulfoxide under anhydrous conditions and heating at 0°C with nomucilnozoum, which was then reacted with 2-dimethylaminoethyl chloride. (Please refer to the above public notice).

However, since the above conventional method uses a reaction between sodium hydride and dimethyl sulfoxide, it has the disadvantage that it cannot be carried out safely on an industrial scale. The yield of the target compound was also low, about 13%.

The present inventors have discovered that co(dermethoxyphenyl)-3-acetyloxy-5-(codimethylanoethyl)-co,
3-dihydro7. ! -Benzothiazepine-+ (5H)
-N-amino alcohol like on/! -We have discovered a method for producing benzothiazepine derivatives on an industrial scale, safely and in high yields, and have completed the present invention.

That is, the present invention provides an α--
Acyloxy-3-(substituted 7enyl i, ?-(coa?
The non-phenylthio)-teropionic acid crocodile conductor is represented by the general formula (wherein X is a halodan atom, and A- is a halodane ion, a boron tetrafluoride ion, l-substituted-, which is an acid ion and is a two-digit lower alkyl group)
α-co-(substituted phenyl)-3 represented by the general formula (wherein X1, -acyloxyco,3-dihydro-7,! -Pensothiazebinda (3H
)-one derivative is obtained, and then fB+ is obtained (in the presence of a phase transfer catalyst and a base) with the general formula (wherein X is a halodane atom, Y is an alkylene group, and R1 and R2 are lower alkyl groups). The general formula (wherein X, , X, , R, R, , R, and Y
is as described above), α--(substituted phenyl)-3-acyloxy-j-(N,N-dialkylannoalkyl)-2,3-dihydro-/.

The present invention relates to a method for producing S-benzothiazepine-4((jH)-one derivatives.

In the present invention, in the above step (α of the formula
-Acyloxy-? The -([0 phenyl)-3-(-1azunophenylthio)-zolopionic acid crocodile conductor can be produced, for example, by adding as follows.

α-”-hydroxy-3-(substituted phenyl)-J-(J
-ditrophenylthio)-furopionic acid derivative (hereinafter abbreviated as propionic acid derivative) is acylated and is represented by the general formula (wherein X, , X, and R are as defined above). α--Acyloxy-3-(substituted 7-enyl)-
A 3-(2-nitro-phenylthio)-teropionic acid derivative (hereinafter abbreviated as nitropropionic acid derivative) is obtained, which is then reduced.

Examples of the propionic acid derivative (VI) include α
-coco-hydroxy-3-phenyl-3-(co-co-hydroxy-3-phenyl-3-
phenylthio)-propionic acid, α-cohydroxy-j-(4'-methoxy-phenyl)-J-(-mono-nitroderchloruphenylthio)-propionic acid,
α-coco-hydroxy-3-methoxy-phenyl)
-,7-(cornitrophenylthio)-propionic acid and the like can be used.

In addition, Xl and X are fluorine and chlorine, respectively.

2) Halo groups such as bromine and halide, 2) lower alkyl groups such as methyl, ethyl, and propyl groups, lower alkoxy groups such as methoxy groups, and nitride groups, and groups such as tetrahydro♂ranyloxy groups. Propionic acid derivatives may also be used. These derivatives (Vl) are
Publication No. 2-1 and Special Publication Sho X 3-/11031! ;
It can be produced according to the method described in the publication.

As the above-mentioned acylating agent, aliphatic carbic acids such as acetic acid, propionic acid, and acetic acid, hydrates of these acids, and acid hydrides can be used.

The reaction between the propionic acid derivative and the acylating agent is as follows: When the acylating agent is an aliphatic carboxylic acid, IJ phosphoric acid, phosphoric anhydride, concentrated sulfuric acid, N,N-dicyclohexylcarboxylate is a diimide group. It is carried out in the presence of a dehydrating agent, and when the acylating agent is an acid hydride, acid halide, etc., pyridine, pyridine, etc. are added in an organic solvent.
It is carried out in the presence of a base such as inodazole, alkali carbonate, or caustic alkali.

Amination of the above-mentioned nitropropionic acid derivative (■) can be carried out using a reducing agent normally used for reducing the nitro group, such as a metal sulfide, a metal polysulfide, a metal such as zinc, iron, or tin, and mineral acids, or a method using palladium charcoal. This can be carried out by a catalytic reduction method using as a catalyst.

In the present invention, the intramolecular ring-closing reaction of the aminopropionic acid derivative (II) is carried out in an organic solvent at room temperature or if necessary in the presence of a l-substituted-cono-ropyridinium salt and a tertiary amine -3; The reaction time is carried out under mild reaction conditions by heating at 0 ocK (Step A). The reaction time differs from 1 depending on the type of ainodelopionic acid derivative, tertiary amine, etc. used, but about /-/ Preferably it is Q time.

The above l-substituted-cohalopyridinium salts include /-methyl-cochloropyridinium iodide,
! -Methyl-copromobilicinium methyl sulfate, l-methyl-copromobilicinium methyl sulfate, l-methyl-copromobilicinium methyl sulfate.

l-ethyl-cope tetramoviridinium tetraphthalate
) r rate etc. may be used. These are prechin, otsu,
De Keken Cal Society of Shirts Q7 No. 30
It can be produced by the method described in 1/163 (1999).

The above l-substituted-cohalopyrizonium radical is used in a molar ratio of about 0 to 0 to the iinobropionic acid derivative ([I).

Examples of the tertiary amino include triethylamino, tributylane, N,N-dimethylcyclohexylane, /,! -Diazobicyclo[ko,ko,ko]octane, /,! f-diadepicic HC3,3,0]-
! t-Nonene, l,g-diazabicycloC! ,'1.
0J-7-undecene etc. can be used.

The tertiary amine b is an aminopropionic acid derivative (II
) is used in an equivalent amount of about 0-co, O-co, :1 to K.

Examples of reaction solvents include N,N-dimethylformand, N,N-nomethylanitand, N-methylpyrrolidone, tetrahydrofuran, coco-methoxyethane, dioxane, acetonitrile, benzene,
Methylene chloride, chloroform, etc. can be used.

The amount of the solvent used is not particularly limited, but it is preferably about 10 to 100 times the volume of the aminopropionic acid derivative.

In the present invention, l obtained as described above.

By reacting S-benzothiazepine derivative (IV) with N,N-dialkylaminoalkyl halide represented by general formula (V) in the presence of a phase transfer catalyst and a base in an organic solvent, N-aminoalkyl-/ .

The 5-t ndzothiazepine crocodile conductor (I) can be prepared (step B), and this reaction is usually carried out at room temperature to about 500 m
It takes about 70 to 30 hours.

Phase transfer catalysts include, for example, II class ammonium salts such as tetra-n-butylammonium iodide, tetra-n-butylammonium iodide and trimethylphenylammonium iodide;

ls-crown-5, dipenzo-/1-crown-6,
Crown ethers such as dicyclohexanor 7g-crown-6 can be used.

The amount of the catalyst used is the usual catalyst amount, for example 1.

3-benzothiazepine derivative (rV) approximately o, o for K
A molar ratio of i to / is sufficient.

As a base, IJ rim (pulverized and oxidized), potassium hydroxide, lithium hydroxide, Fium hydride, etc. are used. Get this base! - Benzothia #♂ene derivative (IV) Used in a molar ratio of about 7 to 20 to K.

As the N,N-dialkylaminoalkyl halide of the above general formula (V), for example! -dimethylaznoethyl chloride, β-diethylaminoethyl chloride, I
-dimethylaminopropyl chloride, l-dimethylaminopropyl chloride, etc. can be used.

The above N,N-dialkylaminoalkyl halide is
1.3-Pyedithia-v1f derivative (TV) Used in a molar ratio of about 1 to K.

Benzene, dichloromethane, carbon tetrachloride, acetonitrile, tetrahydrofuran, etc. can be used as the reaction solvent. There is no particular control over the amount of this solvent used, but l
,! -About / 0 for benzothiazepine derivative ([V)
-j The amount is preferably O times the volume.

Next, the present invention will be explained in more detail with reference to Example 971.

Reference example α-coco-hydroxy-3-dermet (7enyl)
-J-(cornitrophenylthio)-propion warmth, t, op with pyridine! θIIJK was dissolved, and acetic acid chloride i, toy were added dropwise under water cooling. After leaving in the refrigerator overnight, it was poured into ice water and neutralized with dilute hydrochloric acid.

Extract using ethyl acetate, wash the ethyl acetate layer with water, dry with magnesium sulfate, and then! Arrogant Pd
-CIIN was added to perform catalytic reduction.

After the reaction was completed, it was filtered and the solvent was distilled off to give α-coco-acetyloxy-3-dame)-cyphenyl)-3-(co-amino-7-ethio)-propionic acid 1,. Obtained 29 ml.

110361 (+) NMR (CDCJ, -7M8) δ: Ko, / (s, JH)
, J,7(a,jH)Lj(d,/HJ-daHs)
T! r −4′(d, /H, JQHz) −
6. Hiro-ri! (m, //H)! Rν""'cm-": 3 companies 0.3310.mu00
．． /OaX Example 1 α--Asotyloxy-j-($-methoxy-phenyl)-J-(j-amino-phenylthio)-f rhoonic acid O,co001 and to-n-butylamine0. Dissolve 3 tsuku- in N,N-dimethylformamide 10IIjK and add 7-methyl-cochlorobirizonium iodide, Q,/di02,N,N-dimethylformamide S into this.
After adding the solution of d dropwise into the chamber for an additional 3 hours, the 0 reaction solution was added to cold water and extracted using chloroform, and the chloroform solution was washed with 14#1 acid and then with water. After drying with magnesium sulfate, the solvent was distilled off. Ethanol was added to the obtained residue to prepare α-co(
Hiro-methoxy-phenyl)-3-acetyloxyco,
3-dihydro-/,5-benzothiazepine-1 (jH)
-on crystal 0. /If the I got it.

Recrystallize this from ethanol and make it
Crystals of oc were obtained.

Turtle/・3II3 (M+) Analysis value C1, Hl, 04NS (3 da 3. dal) Calculated value C6 Ko, Zoro H-tei, 99 N da, Ot S de,
3 da experimental value Cb3.0 Hiro H3;', 0 Ko N da, Q
789 Slag Example α--(methoxy-phenyl)-3-acetyloxyco, 3-dihydro-/, f-benzothiazepine-
Hiro (5M)-one% cooo*y, potassium hydroxide y'y
, sq, and /1-crown-hydrogen, 20M19 was added to acetonitrile, followed by cozomethylaminoethyl chloride, benzene-toluene/1 to 1.
A solution of the combined solvent Kod was added dropwise over an hour.

At room temperature! After stirring for an hour, the mixture was diluted in ice water and extracted using chloroform (9).The chloroform layer was washed with water, dried, and the chloroform was distilled off. Add ether and 10 esteric acid to the obtained residue, make the soluble portion in IQ dihydrochloric acid alkaline with carbonate, extract again using ether, distill off the ether, and add isopropyl ether to the resulting 9 residue. The precipitated crystals were collected as P.

α--(Siphenyl in goomet)-3-acetyloxy-! -(-1zomethylaminoethyl)-2,3-dihydro-1,! -Crystals of benzothiazepine-4I(6B)-one//II:, 2■ were obtained. This was recrystallized from isopropyl ether to enp/3 da~13 boctr.
>Obtain crystal &e! ! L/@ +z cap u+) Analysis value C
,ff1H□04N,8 (Hiroshi/Hiroshi, 3 pieces) Calculated value
C63, Ri! ;H&, 3 pieces N4.71. S ri, 7
3 Experimental value Cb3. 'Ig H&, 3! f N i
ri/S7. No. 0 Procedures Amendment Book Showa Year Month 111, Indication of the case Showa J6 Patent No. /, 21333 No. 3, Relationship with the case of the person making the amendment Applicant Nihon Iyakuhinfugi One name Nippon Pharmaceutical Industries Co., Ltd. 4, Agent 5, Date of amendment order Voluntary 6゜(1) The scope of claims in the specification is corrected as shown in the attached sheet.

(2) The 7th line from the bottom of page 5 of the same book, the 2nd line from the bottom, and the silk/,
Delete 1 nitro group ' in the 2M/μ line.

(3) 1α-acyluoki/- in the 3rd line from the bottom of No. 70 of the tube book
6 is corrected to "α-noacyloxy-".

Special 11! FtlI! The desired range general formula (wherein X and x2 are each independently a hydrogen atom, a halodane atom, a lower alkyl group or a lower alkoxy group, R
is an alkyl group).

General formula (in the formula, x3 is Hao) f7 atom, ^- is halon ion, boron tetrafluoride ion, para-toluenesulfonic acid ion, methyl sulfate ion% or perchlorate ion, and 2 is / is a lower alkyl group)
-Reacted in the presence of a substituted-2-halopyridinium salt and a tertiary amino (α-λ-CM-substituted phenyl) represented by the general formula (where x, x2 and R are as described above) -3-7 fluo Φ sea 2
．． 3-nohydro/Ij-benzothiazepine 1ltC
jH)-one derivative is obtained, which is then subjected to the general formula (wherein XFi is a halon atom, Y is an alkylene group, R and RFi are lower alkyl groups) in the presence of a phase transfer catalyst and a base. l
It is characterized by allowing N,N-zoalkylaminoalyhalide represented by 2 to act.

α-2-(substituted phenyl)-3-acyloquita-3;-(N , N-zoalkyla( (noalkyl)-λ, 3-dihydro-/, j-pe/
Method for producing zothiazepine-4t(jH)-one derivative.

Claims (1)

[Scope of Claims] In the general formula c, x1 and -coco-acyloxy-3-substituted phenyl)-j-(co-amino-phenylthio)-teropionic acid derivative with the general formula (wherein X is halo) f7 [child, A- is halo r
ion, boron tetrafluoride ion, )radluenesulfonate ion, methyl sulfate ion, or perchlorate ion, and 2 is a lower alkyl group).
α-co(f-substituted phenyl) represented by the general formula (wherein X1, -3-acyloxy-cotton 3-dihydro-/, J-penzothiazepinda (jH
)-one derivative is obtained, which is then treated with the general formula (where X is a halo Jf7 atom, YFi is an alkylene group, and R1 and R2 are lower alkyl groups) in the presence of a phase transfer catalyst and a base. of the general formula (wherein X, , X, , R, R, , R, and Y
α--(Substituted 7-enyl)-3-acyloxy-,! -(N,N-dialkyladenoalkyl)-2,,7-sihydrol. ! -Production method of benzothiazepine-tei (jH)-one derivative.