CN1031229A - 1.5-the preparation method of benzothiazepine cycloheptane derivative class - Google Patents

1.5-the preparation method of benzothiazepine cycloheptane derivative class Download PDF

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CN1031229A
CN1031229A CN88104387A CN88104387A CN1031229A CN 1031229 A CN1031229 A CN 1031229A CN 88104387 A CN88104387 A CN 88104387A CN 88104387 A CN88104387 A CN 88104387A CN 1031229 A CN1031229 A CN 1031229A
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benzothiazepine
preparation
formula
compound
derivative
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CN1030570C (en
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井上博纯
原田恒博
长泽正明
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Tanabe Seiyaku Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring

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  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A kind of preparation method of the 1.5-benzothiazepine cycloheptane derivative class by following structural formula (I) expression: in the formula:
R 1Be low alkyl group or lower alkoxy,
R 2Be hydrogen or lower alkane acyl group,
R 3And R 4One be low alkyl group or halogen atom, and another is hydrogen, and
R 5And R 6Each be low alkyl group or a kind of pharmaceutically acceptable its salt of sour addition,
It is characterized in that: comprise the compound with said structure formula (II) expression: and the amine compound of a kind of said structure formula representative reacts: and change it if desired and become a kind of pharmaceutically acceptable its salt of sour addition.

Description

1.5-the preparation method of benzothiazepine cycloheptane derivative class
The present invention relates to 1.5-(benzothiazepine suberane) preparation method of derivatives class and pharmaceutically acceptable salt thereof, it is useful as compound pharmaceutically, and represents by following structural formula:
In the formula: R 1Be low alkyl group or lower alkoxy,
R 2Be hydrogen or lower alkane acyl group,
R 3And R 4One be that low alkyl group or halogen atom and another are hydrogen, and
R 5And R 6Each be low alkyl group.
1.5-the salt of benzothiazepine suberane (I) and pharmaceutically acceptable sour addition thereof is to have the vasorelaxation or the coronary vasodilation activity of excellent antihypertensive activity, brain and/or suppress the active useful pharmaceutical compound of platelet aggregation, in compound (I), R in the formula 2During for hydrogen atom, also be the useful intermediates during a kind of medicine synthesizes.
Can comprise among the embodiment of compound of the present invention (I) that the R in compound is low alkyl group or lower alkoxy, R 2Be hydrogen or lower alkane acyl group, R 3Or R 4In one be low alkyl group or halogen atom, and another is hydrogen atom, and R 5And R 6Each be low alkyl group.
In the embodiment of the above-mentioned 1.5-benzothiazepine cycloheptane derivative of mentioning (I); this low alkyl group, lower alkoxy and lower alkane acyl group represent to comprise the alkyl of 1 to 6 carbon atom; the alkoxyl group of 1 to 6 carbon atom, and the alkanoyl of 1 to 6 carbon atom.
The preferred embodiment of these groups is the alkoxyl group of the alkyl of 1 to 4 carbon atom, 1 to 4 carbon atom and the alkanoyl of 2 to 5 carbon atoms.
According to the present invention, compound (I) or its pharmaceutically acceptable salt, the compound that can represent by following structural formula:
Figure 881043877_IMG7
X is active residue in the formula, and R 1, R 2, R 3And R 4The amine of representing as above-mentioned defined and following structural formula:
Figure 881043877_IMG8
R in the formula 5And R 6As above-mentioned defined or the preparation of its reactant salt, can change it if needed and become a kind of pharmaceutically acceptable its salt.
The reaction of compound (II) and amine (III) or its salt can be carried out in the existence of alkali or not in a kind of suitable solvent.In compound (II), the example of the active residue of being represented by X can comprise halogen atom, such as: fluorine atom, chlorine atom, bromine atoms and iodine atom, alkylsulfonyloxy, for example: sulfonyloxy methyl oxygen base, and phenyl sulfonyloxy that replace or non-replacement, for example: tosyloxy.Simultaneously, amine (III) can also can be used for above-mentioned reaction with its salt with unbound state.The example of these salt can comprise traditional acid salt, such as: hydrochloride, hydrobromide, vitriol, nitrate etc.As alkali, they can be suitable mentioned alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate, tertiary amine etc., and compound (III) also can be used for this purpose.Reaction of the present invention preferably in a kind of suitable solvent (for example: dimethyl formamide; diethylformamide; N,N-DIMETHYLACETAMIDE; the N-formyl morpholine; N-ethanoyl morpholine; dimethyl sulfoxide (DMSO); diglyme; diethyl ether; tetrahydrofuran (THF); glycol dimethyl ether diox; pyridine; alkanol; acetonitrile; acetone; methyl ethyl ketone; ethyl acetate; methyl acetate; methyl propionate; ethyl propionate; benzene; dimethylbenzene; toluene etc.) between 0 ℃ and 150 ℃ of temperature, carry out.
The compound that obtains thus (I) can easily be transformed into a kind of salt of pharmaceutically acceptable sour addition, for example: if desired, by using a kind of acid treatment.The example of the salt of these pharmaceutically acceptable sour additions comprises: the salt of mineral acid addition, such as: hydrochloride, hydrobromide, hydriodide, perchlorate, vitriol, phosphoric acid salt etc.; And the salt of organic acid addition, such as: oxalate, maleate, tartrate, metilsulfate etc.
By the bright bucktooth scheme convulsion ⒚ that remonstrates with tan from Φ nurse green pepper ǎ ü  send waste extensive  Cannibals  hold in the mouth the good polished Chi tip edge rose of polished á Ying ┳ Chi  fish hawk take off extensive in  Cannibals  hold in the mouth polished á scar   convulsion to talk about the tree of heaven sister-in-law ⑸  Wei Wei  of anti-arrange  cooked food from Σ disrespectful
Of the present invention 1, the salt of 5-benzothiazepine cycloheptane derivative class (I) or its pharmaceutically acceptable sour addition, have the antihypertensive activity of excellence as mentioned above, the vasorelaxation of brain or the activity of coronary vasodilation activity and/or inhibition platelet aggregation, and can be used for treating disease with prevention of brain, for example: cerebrovascular contraction, brain local anemia, cerebrum block etc., or heart disease, for example: stenocardia, myocardial infarction etc.Simultaneously, in the compound (I), the R in the compound formula 2When being hydrogen atom, also be useful, because this compound can be the R in the compound (I) by acylation as synthetic intermediate 2Be transformed into the lower alkane acyl group.
Compound of the present invention (II) can be by the compound of being represented by following structural formula:
Figure 881043877_IMG9
R in the formula 1, R 2, R 3And R 4As above-mentioned defined, it can method according to the above description obtain, for example, in the interim patent publication No. No.225174/1984 of Japan, the compound of representing with following structural formula:
X is active residue and X such as above-mentioned defined in the formula, (for example: (for example: alkali metal hydroxide, alkalimetal hydride) reacts dimethyl sulfoxide (DMSO)) in the presence of alkali in suitable solvent, if desired, product further carries out condensation reaction with the reactive derivative (for example: acid anhydrides, etheride) of lower fatty acid.
Simultaneously, compound of the present invention (I) and compound (II) comprise two kinds of steric isomers (that is: cis and trans-isomer(ide)) or four kinds of optical isomers (that is: (
Figure 881043877_IMG10
)-cis, (-)-cis, ( )-trans and (-)-trans-isomer(ide)) and based on their mixture of two unsymmetrical carbons in molecule.
Embodiment 1
(1) in containing 50 milliliters dimethyl sulfoxide (DMSO) of 590 milligrams of potassium hydroxide the dissolving 3.36 the gram (
Figure 881043877_IMG12
)-suitable-2-(4-p-methoxy-phenyl)-3-hydroxyl-8-chloro-2.3-dihydro 1.5 benzothiazepine suberane-4(5H)-ketone, this solution stirred under room temperature 30 minutes.Then, stir under room temperature to these solution adding 1.75 gram 1-chloro-2-methylsulfonyl oxidative ethanes and this mixture.After reacting completely, this mixture is poured in ice-water, and uses ethyl acetate extraction.Extraction liquid washes with water, dry and boil off solvent then.This residue is dissolved in the ether relief, and it leaves standstill, by removing by filter insoluble starting material.This filtered liquid concentrates to remove and desolvates.The oily matter that obtains by the silica gel column chromatography purifying (solvent, chloroform: ethyl acetate=20: 1), and from ethanol recrystallization, obtain 1.05 the gram) ( )-suitable-2-(4-p-methoxy-phenyl)-3-hydroxyl-5-(2-chloroethyl)-8-chloro-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone and ( )-suitable-2-(4 p-methoxy-phenyl)-and 3-hydroxyl-5-[2-(methylsulfonyl oxygen) ethyl]-8-chloro-2,3-dihydro-1.5-benzothiazepine suberane)-4(5H)-alcohol/ketone mixtures (9: 1).
Fusing point: 125 to 128 ℃
MS（m/e）：365，363（M +-CH 3SO 2）
(2) 1.03 gram the said products are dissolved in 10 milliliters of dimethyl formamides, and add dimethylamine-toluene solution of 90 milligram 51% to this solution, this mixture stirred under room temperature 62 hours.Dimethylamine-the toluene solution that adds 180 milligram 51% further to this mixture, and this mixture stirs under room temperature.After reacting completely, add entry and with this mixture of ethyl acetate extraction to this mixture.Extraction liquid washes with water, and dry, under reduced pressure removes then and desolvates.Residue by the silica gel column chromatography purifying (solvent, chloroform: ethanol=95: 5) and from ethyl acetate and just-mixed solvent of hexane recrystallization, obtain 687 milligrams (
Figure 881043877_IMG15
)-suitable-2-(4-p-methoxy-phenyl)-and 3-hydroxyl-5-[2-(dimethylamino) ethyl]-8-chloro-2,3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone.
Fusing point: 122 to 124 ℃ (decomposition).
Embodiment 2
(1) dissolving 10.08 gram (+)-suitable-2-(4-p-methoxy-phenyls in 150 milliliters of dimethyl sulfoxide (DMSO) that contain 1.77 gram potassium hydroxide)-3-hydroxyl-8-chloro-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone, and this solution stirred under room temperature 30 minutes.Then, add 4.70 gram 1-bromo-2-monochloroethane to this solution, and this mixture stirs under room temperature.After reacting completely, in this mixture impouring ice-water, and use ethyl acetate extraction.Extraction liquid washes with water and is dry, boils off solvent.Residue is dissolved in the ether and allows it leave standstill then, and sedimentary initial material is by removing by filter.Filtered liquid concentrates to remove most solvent.Residue left standstill and, obtain 594 milligrams of crude products by filtering the crystallization of coming out with collecting precipitation.This filtered liquid adopt silica gel chromatography (solvent, chloroform: ethyl acetate=20: 1) and the crude product that obtains and above gained crude product merge.Their recrystallizations from ethanol obtain 7.94 the gram (
Figure 881043877_IMG16
)-suitable-2-(4-p-methoxy-phenyl)-3-hydroxyl-5-(2-chloroethyl)-8-chloro-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone.
Fusing point: 128 to 131 ℃
IRν Nujol max（cm）：3460，1660，1590.
MS（m/e）：399，397（M +）
(2) this product is in dimethylamine-toluene solution of 51% and dimethyl formamide reaction, and uses embodiment 1-(2) same procedure prepare (
Figure 881043877_IMG17
)-suitable-2-(4-p-methoxy-phenyl)-and 3-hydroxyl-5-[2-(dimethylamino) ethyl]-8-chloro-2,3-dihydro-1.5-benzothiazepine suberane-4-(5H)-ketone,
Fusing point: 122 to 124 ℃ (decomposition)
Embodiment 3.
In the mixture of 3 ml acetic anhydride and 2 milliliters of acetate, add 484 milligrams (
Figure 881043877_IMG18
)-suitable-2-(4-p-methoxy-phenyl)-3-hydroxyl-5-(2-chloroethyl)-8-chloro-2.3-dihydro-1.5-benzothiazepine suberane-4-(5H)-ketone, this mixture stirs down in 110 ℃.After reacting completely, mixture under reduced pressure concentrates to remove and desolvates.Residue is dissolved in the toluene, under reduced pressure it is concentrated into dried, obtain 535 milligrams ( )-suitable-2-(4-p-methoxy-phenyl)-3-acetoxyl group-5-(2-chloroethyl)-8-chloro-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone, be the oily product.
IRν liq max（cm）：1740，1680，1600，1580.
MS（m/e）：439，441（M +）
(2) above-mentioned product is in 51% dimethylamine-toluene solution and dimethyl formamide reaction, and use embodiment 1-(2) same procedure prepare, obtain (
Figure 881043877_IMG20
)-suitable-2-(4-p-methoxy-phenyl)-and 3-acetoxyl group-5-[2-(dimethylamino) ethyl]-8-chloro-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone.The maleate of product:
Fusing point: 159 to 160 ℃ (recrystallization from ethanol)
Embodiment 4 to 9
With the identical method of embodiment 1 to 3,, can obtain following compound by handling corresponding starting material:
(4) ( )-suitable-2-(4-p-methoxy-phenyl)-and 3-hydroxyl-5-[2-(dimethylin) ethyl]-9-chloro-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone.
Perchlorate 1/4 hydrate:
Fusing point: 190 to 192 ℃
(5) ( )-suitable-2-(4-p-methoxy-phenyl)-and 3-acetoxyl group-5-[2-(dimethylamino) ethyl]-9-chloro-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone.
Hydrochloride monohydrate: fusing point: 140 to 143 ℃
(6) (±)-suitable-2-(4-tolyl)-and 3-hydroxyl-5-[2-(dimethylamino) ethyl]-8-methyl-2,3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone,
Fusing point: 142 to 143 ℃ (recrystallization from ethyl acetate).
(7) (±)-suitable-2-(4-tolyl)-and 3-acetoxyl group-5-[2-(dimethylamino) ethyl]-8-methyl-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone.
Hydrochloride:
Fusing point: 184 to 186 ℃ (recrystallization from the mixed solvent of Virahol and ether)
This product, when recrystallization from acetone and isopropyl ether mixed solvent, fusing point is 190 to 192 ℃, like this, this product has the character of xln polymorphism.
The fumarate of product:
Fusing point: 196.5 to 198.5 ℃ (decomposition) (from Virahol recrystallization)
The maleate of product:
Fusing point: 173.5 to 175.5 ℃ of (decomposition) (from ethyl alcohol recrystallizations)
This product, when recrystallization from methyl alcohol, fusing point is 172.5 to 174 ℃, and when recrystallization from water, the crystalline fusing point that draws is 191.9 ℃, like this, this product has the character of xln polymorphism.
The metilsulfate of product:
Fusing point: 124 to 128 ℃ (from Virahol recrystallization).
(8) (+)-suitable-2-(4-tolyl)-and 3-acetoxyl group-5-[2-(dimethylamino) ethyl]-8-methyl-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone,
Maleate:
Fusing point: 194 to 197 ℃ (decomposition) (recrystallization from ethanol)
[α] 20 D+ 83.7 ° (C=0.362, methyl alcohol)
The oxalate of product:
Fusing point: 179 to 180 ℃ (recrystallization from ethanol)
[α] 20 D=88.2 ° (C=0.288, methyl alcohol)
(9) (-)-suitable-2-(4-tolyl)-and 3-acetoxyl group-5-[2-(dimethylamino) ethyl]-8-methyl-2.3-dihydro-1.5-benzothiazepine suberane-4(5H)-ketone,
Oxalate:
Fusing point: 179.5 to 181 ℃ (decomposition) (recrystallization from ethanol)
[α] 20 D-83.8 ° (C=0.333, methyl alcohol)
The maleate of product:
Fusing point: 195 to 197.5 ℃ (decomposition) (recrystallization from ethanol)
[α] 20 D-83.6 ° (C=0.50, methyl alcohol)
The fumarate of product:
Fusing point: 210.5 to 212.5 ℃ (decomposition) (recrystallization from ethanol)
[α]-91.3 ° (C=0.323, methyl alcohol)
The L-(of product )-tartrate:
Fusing point: 140 to 143 ℃ (recrystallization from the mixed solvent of ethanol and ether).

Claims (8)

1, a kind of preparation method of the 1.5-benzothiazepine cycloheptane derivative class of representing by following structural formula:
In the formula:
R 1Be low alkyl group or lower alkoxy,
R 2Be hydrogen or lower alkane acyl group,
R 3And R 4One be low alkyl group or halogen atom, and another is hydrogen, and
R 5And R 6Each be low alkyl group or a kind of pharmaceutically acceptable its salt of sour addition,
It is characterized in that: comprise the compound that following structural formula is represented:
Figure 881043877_IMG3
R in the formula 1, R 2, R 3And R 4As above-mentioned defined, and X is the amine compound reaction of active residue and the representative of a kind of following structural formula:
Figure 881043877_IMG4
R in the formula 5And R 6As above-mentioned defined or its salt, and change it if desired and become a kind of pharmaceutically acceptable its salt of sour addition.
2, the preparation method of 1.5-benzothiazepine cycloheptane derivative as claimed in claim 1 is characterized in that in solvent in the existence of alkali or reacts between 0 ℃ and 150 ℃ of temperature not.
3, the preparation method of 1.5-benzothiazepine cycloheptane derivative as claimed in claim 2 is characterized in that described alkali is alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate or tertiary amine.
4, the preparation method of 1.5-benzothiazepine cycloheptane derivative as claimed in claim 1 is characterized in that the reaction residue that X represents is halogen atom, alkylsulfonyloxy or phenyl sulfonyloxy that replace or non-replacement.
5, the preparation method of 1.5-benzothiazepine cycloheptane derivative as claimed in claim 1, the salt that it is characterized in that described amine is hydrochloride, hydrobromate, sulfuric acid or the nitrate of amine.
6, the preparation method of 1.5-benzothiazepine cycloheptane derivative as claimed in claim 2 is characterized in that described solvent is selected from and comprises dimethyl formamide, diethylformamide, N,N-DIMETHYLACETAMIDE, N-formyl morpholine, N-ethanoyl morpholine, dimethyl sulfoxide (DMSO), diglyme, diethyl ether, tetrahydrofuran (THF), glycol dimethyl ether, diox, pyridine, alkanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, methyl acetate, methyl propionate, ethyl propionate, benzene, dimethylbenzene and toluene.
7, the preparation method of 1.5-benzothiazepine cycloheptane derivative as claimed in claim 1 is characterized in that the compound that described structure formula II is represented, by compound with following structural formula representative:
R in the formula 1, R 3And R 4Compound as defined in claim 1 and following structural formula representative:
To be active residue have identical meaning with X in claim 1 regulation to X in the formula, in solvent, react in the presence of alkali, and product further carries out condensation reaction with the reactive derivative of lower fatty acid if desired.
8, the preparation method of 1.5-benzothiazepine cycloheptane derivative as claimed in claim 7, the reactive derivative that it is characterized in that described lower fatty acid is acid anhydrides or etheride.
CN88104387A 1987-08-12 1988-07-11 Process for preporing 1.5-benzothiazepine eerivatives Expired - Fee Related CN1030570C (en)

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JP62202027A JPS6445376A (en) 1987-08-12 1987-08-12 Production of 1,5-benzothiazepine derivative
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GB1236467A (en) * 1967-10-28 1971-06-23 Tanabe Seiyaku Co Benzothiazepine derivatives
US3895006A (en) * 1974-04-19 1975-07-15 Squibb & Sons Inc 5-(Substituted amino)alkyl)-2-aryl-3-halo-1,5-benzothiazepin-4(5H)-ones
SE449611B (en) * 1982-07-09 1987-05-11 Tanabe Seiyaku Co SET TO MAKE 1,5-BENZOTIAZEPINE DERIVATIVES
GB8315364D0 (en) * 1983-06-03 1983-07-06 Tanabe Seiyaku Co 8-chloro-1 5-benzothiazepine derivatives
US4567175A (en) * 1983-06-03 1986-01-28 Tanabe Seiyaku Co., Ltd. 8-Chloro-1,5-benzothiazepine derivatives
GB8406318D0 (en) * 1984-03-10 1984-04-11 Tanabe Seiyaku Co 1 5-benzothiazepine derivatives
JPS60204776A (en) * 1984-03-30 1985-10-16 Roller Japan Kk 1,5-benzothiazepine derivative
JPS61103877A (en) * 1984-10-24 1986-05-22 Tanabe Seiyaku Co Ltd Benzothiazepine derivative and its preparation

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GR880100515A (en) 1989-05-25
NO883525L (en) 1989-02-13
PT88250B (en) 1995-03-01
CA1337346C (en) 1995-10-17
NO883525D0 (en) 1988-08-09
SU1709908A3 (en) 1992-01-30
PT88250A (en) 1989-06-30
GR1000385B (en) 1992-06-30
IE881949L (en) 1989-02-12
JPS6445376A (en) 1989-02-17
ES2007990A6 (en) 1989-07-01
KR890003722A (en) 1989-04-17
CN1030570C (en) 1995-12-27
IL86978A0 (en) 1988-12-30
BG50501A3 (en) 1992-08-14
AT395010B (en) 1992-08-25
NO170017B (en) 1992-05-25
FI883115A0 (en) 1988-06-29

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