CA1291134C - Process for preparing 1,5-benzothiazepine derivatives - Google Patents
Process for preparing 1,5-benzothiazepine derivativesInfo
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- CA1291134C CA1291134C CA000526793A CA526793A CA1291134C CA 1291134 C CA1291134 C CA 1291134C CA 000526793 A CA000526793 A CA 000526793A CA 526793 A CA526793 A CA 526793A CA 1291134 C CA1291134 C CA 1291134C
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- lower alkyl
- compound
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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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- 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
Abstract:
The invention provides a novel process for preparing 1,5-benzothiazepine derivatives of the formula:
The invention provides a novel process for preparing 1,5-benzothiazepine derivatives of the formula:
Description
_ el process for preparing 1,5-benzothiaze~ine derivatives This invention relates to a novel process for preparing l,5-benzothiazepine derivatives of the formula:
Cl ~ OR' OR Z
O CH~
CHzCH2N /
X ' wherein Rl is a lower alkyl group, R is hydrogen atom or a lower alkanoyl group, and Xl is hydrogen atom or a lower alkyl group, or a salt thereof.
U.S~. Patent 3,562,257 discloses vario~s benzothiazepine derivatives including~7-chloro-1,5-benzothiazepine deriv-atives such as 2-(4-methoxyphenyl)-3-hydroxy(or acetoxy)-S-t2-(dimethylamlno)ethyl]-7-chloro-2,3-dihydro-1~5-benzo-thiazepin-4(5H)~-one. The aforesaid U.S. Patent also discloses~ that these benzothiazepine derivatives have antidepressive,~tranquilizing and/or coronary vasodilating activities~
~As compared with these known compounds, the compounds (I)~of the~ pr~esent~lnventi~on in which Xl is a lower alkyl~group show stronger hypotensive and cerebral or ..
.
` :
Cl ~ OR' OR Z
O CH~
CHzCH2N /
X ' wherein Rl is a lower alkyl group, R is hydrogen atom or a lower alkanoyl group, and Xl is hydrogen atom or a lower alkyl group, or a salt thereof.
U.S~. Patent 3,562,257 discloses vario~s benzothiazepine derivatives including~7-chloro-1,5-benzothiazepine deriv-atives such as 2-(4-methoxyphenyl)-3-hydroxy(or acetoxy)-S-t2-(dimethylamlno)ethyl]-7-chloro-2,3-dihydro-1~5-benzo-thiazepin-4(5H)~-one. The aforesaid U.S. Patent also discloses~ that these benzothiazepine derivatives have antidepressive,~tranquilizing and/or coronary vasodilating activities~
~As compared with these known compounds, the compounds (I)~of the~ pr~esent~lnventi~on in which Xl is a lower alkyl~group show stronger hypotensive and cerebral or ..
.
` :
coronary vasodilating activities and are more useful for the treatment, amelioration and/or prophylaxis of hypertension; cerebral diseases such as cerebral vasospasm or cerebral infarction; and heart diseases such as angina pectoris, arrhythmia or myocardial infarction. On the other hand, the compounds (I) of the invention in which X is a hydrogen atom show platelet aggregation-inhibiting activity and are useful for the treatment, amelioration and/or prophylaxis of thrombotic diseases such as cerebral thrombosis (cerebral infarction), tran-sient cerebral ischemia, coronary thrombosis (myocardial infarction), pulmonary embolism, peripheral vascular embol-ism, thromboangiitis and/or other thromboembolism (e.g.
the thromboembolism following heart valve replacement).
According to the present invention, the compounds (I) can be prepared by:
i) alkylating a compound of the formula:
Cl ~ OH
CHzCH2N <
wherein R is a hydrogen atom or a lower alkanoyl group ~ and x2 is a hydrogen atom, a lower alkyl group or a protecting group;
ii) when X is a protecting group, removing said protecting group therefrom;
iii) when R3 is a lower alkanoyl group, optionally removing said lower alkanoyl group therefrom and iv) if required, further converting the product into a salt thereof.
.
:
the thromboembolism following heart valve replacement).
According to the present invention, the compounds (I) can be prepared by:
i) alkylating a compound of the formula:
Cl ~ OH
CHzCH2N <
wherein R is a hydrogen atom or a lower alkanoyl group ~ and x2 is a hydrogen atom, a lower alkyl group or a protecting group;
ii) when X is a protecting group, removing said protecting group therefrom;
iii) when R3 is a lower alkanoyl group, optionally removing said lower alkanoyl group therefrom and iv) if required, further converting the product into a salt thereof.
.
:
In the above-mentioned reactions, a wide variety of protecting groups normally employed to protect amino groups may be used as the protecting group X~. Examples of such protecting groups include unsubstituted or sub-stituted benzyloxycarbonyl groups e.g. benzyloxycarbonylor p-methoxybenzyloxycarbonyl groups; unsubstituted or substituted lower alkoxycarbonyl groups e.g. tert.-butoxycarbonyl, ~ -trichloroethoxycarbonyl or iodoethoxycarbonyl groups; and unsubstituted or substituted phenyl-lower alkyl groups e.g. benzyl, p-methoxybenzyl or 3,4-dimethoxybenzyl groups.
The alkylation reaction of this invention can be carried out by treating the compound (II) with a low~r alkylating agent. Such an alkylating agent may be, for example, a lower alkanol, a lower alkyl sulfate e.g.
dimethylsulfate, a lower alkyl ester of alkyl or aryl sulfonate e.g. methyl tosylate, methyl methanesulfonate and dimethyl 2-oxo-1,3-propane disulfonate, a lower alkyl halide e.g. methyl iodide and methyl bromide, a lower alkyl quaternary ammonium compound e.g. trimethylphenyl-ammonium hydroxide, a lower alkyl sulfonium or sulfoxonium compound e.g. trimethylsul~onium hydroxide, trimethyl-sulfoxonium iodide, a lower alkyl selenonium compound e.g.
trimethylselenonium hydroxide, and a diazo lower alkane e.g. diazomethane.
When a lower~alkanol is used as the alkylating agent, the reaction is preferably carried out in the presence of a dehydrating agent. Conventional dehydrating agents, e.g. dicyclohexylcarbodiimide or a mixture of triphenyl-phosphine and diazenedicarboxylic acid diethyl ester, maybe used for this purpose. The reaction is preferably carried out at temperature of 0 to 40C.
When the above-mentioned lower alkyl sulfate, lower alkyl ester of alkyl or aryl sulfonate or lower alkyl halide is used as the alkylating agent, the reaction is preferably carried out in the presence of a base. Examples of the base include inorganic bases e.g. an alkali metal p~
oxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydride or an alkali metal alkoxide, and organic bases e.g. ethyl diisopropyl amine.
The reaction is preferably carried out at a temperature between OC and the refluxing temperature, and especially at 10 to 40C in an inert solvent (e.g., acetone, acetonitrile, methanol, benzene, dioxane, tetrahydroEuran, dimethylsulfoxide, dimethylformamide). The reaction is also preferably carried out in the presence of a phase-transfer catalyst e.g. tetrabutylammonium fluoride.
On the other hand, when the lower alkyl quaternary ammonium compound, lower alkyl sulfonium or sulfoxonium compound or lower alkyl selenonium compound is used as the alkylating agent, the reaction is preferably carried out at a temperature between 10C and the refluxing tempera-ture, and especially at 50~100C, either in an inert solvent or without a solvent. Toluene, dioxane, methanol, dimethylformamide and dimethylsulfoxide are suitable solvents.
When the diazo lower alkane is used as the alkylating agent, the reaction is preferably carried out at a temperature of 0 to 40C, and especially 20 to 30C, in an inert solvent. Dioxane, tetrahydrofuran, methanol and mixtures thereof are suitable as the solvent. When the group R3 of the starting compound ~II) is a lower alkanoyl group, the reaction is preferably carried out in the presence of fluoroboric acid or silica gel.
When carrying out the above-mentioned alkylation reaction, it is particularly preferred to use the lower alkyl sulfate, lower alkyl sulfonate or lower alkyl halide as the alkylating agent when the group x2 of the ~ 5 ~3~
starting compound (II) is a hydrogen atom and the group R is the lower alkanoyl group; or alternatively it is particularly preferable to use the lower alkyl quaternary ammonium compound, lower alkyl sul~onium or sulfoxonium compound, lower alkyl selenonium compound or diazo lower alkane as the alkylating agent when both the groups x2 and R3 of the starting compound (II) are a hydrogen atom.
When the group x2 of the thus-obtained product is a protecting group, removal of the protecting group may be conducted in a conventional manner. For example, when the protecting group is an unsubstituted or substituted benzyloxycarbonyl or unsubstituted lower alkoxy carbonyl, the group may be readily removed by treating the compound with an acid e.g. hydrogen bromide, hydrogen chloride or trifluoroacetic acid in a solvent. When the protecting group is a substituted lower alkoxy carbonyl, the group may be removed by treatment with zinc in a solvent. On the other hand, when the protecting group is an unsubstituted or substituted phenyl lower alkyl, the group may be removed by first substituting it with a protecting group (e.g., benzyloxycarbonyl group) which is readily removable with an acid, and then treating the latter group in the same manner as mentioned above. Substitution of the unsubstituted or substituted phenyl lower alkyl with the benzyloxycarbonyl group is pre~erably carried out by treating the product (i.e., the compound in which the imino group is protected by the unsubstituted or substituted phenyl lower alkyl group) with benzyloxycarbonyl halide, e.g. benzyloxycarbonyl chloride, at a temperature between 50 and 130C in a solvent.
When R3 is the lower alkanoyl group, the protecting group and the lower alkanoyl group may be removed simul-taneously, or the protecting group may be removed without removal~ of the lower alkanoyl group. These reactions can be controlled by changing the reaction conditions, e.g.
the amount of the reaction agents, the reaction time and/or the reaction solvent used.
- 6 ~
If required, the compound (I) of the present invention thus obtained may be converted into its acid addition salts by treating it with an acid. Examples of the acid addition salts include inorganic acid addition salts e.g.
hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate or phosphate, organic acid addition salts e.g.
oxalate, maleate, fumarate or methanesulfonate, and so forth.
Since the above-mentioned reactions of the invention can be carried out without racemization, the compound (I) in an optically active form can be readily obtained by the use of an optically active isomer of the comp~nd (II) as the starting compound.
The starting compound (II) may be prepared, for lS example, by: reacting 3-(4-benzyloxyphenyl)glycidic acid methyl ester with 5-chloro-2-aminothiophenol to give 2-(4-benzyloxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one or a salt thereof; condensing the product with a compound of the formula:
" , CH3 Y CH2CH2N (III) wherein Y is a halogen atom and x2 is the same as defined above, or a salt thereof, to give a compound of the formula:
Cl ~ ~ O-CH2 ~
OH (IV) I O CH
CH2CHzN /
~X 2 .
- 7 ~
wherein x2 is the same as defined above; removing the benzyl group Erom the compound (IV); and if required, converting the hydroxy gro~p of the thus-obtained product at the 3-position of the benzothiazepine ring into a lower alkanoyloxy group before or after removal of the benzyl ~roup.
The compound ~I) and the starting compound (II) can exist in the form of two diastereoisomers (e.g., cis and trans) or four optical isomers (e.g., (+)-cis, (-)-cis, (+)-trans, and (-)-trans) due to the two asymmetric carbon atoms involved therein, and all of these isomers and mixtures thereof are included within the scope o~ the invention. Among these isomers, however, the cis isomer o~ the compound (I) is pre~erred for medicinal use.
Presently preferred embodiments of the invention are described in detail in the following Examples which should not be construed as limiting.
Example 1 690 mg of (+)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2-(N,N-dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were dissolved in 20 ml of tetrahydrofuran. Sodium hydride (78 mg, 60% oily) was added thereto at room temperature and the mixture was stirred ~or 30 minutes at the same temperature. A
solution of 245 mg of dimethyl sul~ate in 10 ml of dimethylformamide was added thereto, and the mixture was stirred ~or 1 hour at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from a mixture of ethyl acetate and n-hexane. The product was 509 mg of (~)-cis-2-~4-methoxyphenyl)-3-hydroxy-5-12-(N,N-dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
M.p. 122-124C (decomp.) [~] D0 +144.6 (C=0.85, methanol) Examples 2 to 4 The corresponding starting compounds were treated in the same manner as described in Example 1 to gi~e the compounds shown in Table 1.
Table 1 Cl S ~ OH Cl S ~ OR' OR3 ~ ~ oR2 I O CH3 ~ O CH3 CHzCH2N / CHzCHzl~ /
(Il) \XZ ( I ) ~X' (R', X' and XZ- -CH3, R3= RZ) Ex. Compound ~I) Optlcal Properties No. R activity .
2: -H cis-(-) M.p. 121-123C (decomp.) : ~20 -142.70(c=l 04 _ D methanol) 3 -COCH3 ~ cis-~+) Maleate(recrystallized ~rom ~ etha.nol-ether) : : M.p. 158-160C
_ ~ ~ ( )2~75 4 (C=1.0,methanol) ~
The alkylation reaction of this invention can be carried out by treating the compound (II) with a low~r alkylating agent. Such an alkylating agent may be, for example, a lower alkanol, a lower alkyl sulfate e.g.
dimethylsulfate, a lower alkyl ester of alkyl or aryl sulfonate e.g. methyl tosylate, methyl methanesulfonate and dimethyl 2-oxo-1,3-propane disulfonate, a lower alkyl halide e.g. methyl iodide and methyl bromide, a lower alkyl quaternary ammonium compound e.g. trimethylphenyl-ammonium hydroxide, a lower alkyl sulfonium or sulfoxonium compound e.g. trimethylsul~onium hydroxide, trimethyl-sulfoxonium iodide, a lower alkyl selenonium compound e.g.
trimethylselenonium hydroxide, and a diazo lower alkane e.g. diazomethane.
When a lower~alkanol is used as the alkylating agent, the reaction is preferably carried out in the presence of a dehydrating agent. Conventional dehydrating agents, e.g. dicyclohexylcarbodiimide or a mixture of triphenyl-phosphine and diazenedicarboxylic acid diethyl ester, maybe used for this purpose. The reaction is preferably carried out at temperature of 0 to 40C.
When the above-mentioned lower alkyl sulfate, lower alkyl ester of alkyl or aryl sulfonate or lower alkyl halide is used as the alkylating agent, the reaction is preferably carried out in the presence of a base. Examples of the base include inorganic bases e.g. an alkali metal p~
oxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydride or an alkali metal alkoxide, and organic bases e.g. ethyl diisopropyl amine.
The reaction is preferably carried out at a temperature between OC and the refluxing temperature, and especially at 10 to 40C in an inert solvent (e.g., acetone, acetonitrile, methanol, benzene, dioxane, tetrahydroEuran, dimethylsulfoxide, dimethylformamide). The reaction is also preferably carried out in the presence of a phase-transfer catalyst e.g. tetrabutylammonium fluoride.
On the other hand, when the lower alkyl quaternary ammonium compound, lower alkyl sulfonium or sulfoxonium compound or lower alkyl selenonium compound is used as the alkylating agent, the reaction is preferably carried out at a temperature between 10C and the refluxing tempera-ture, and especially at 50~100C, either in an inert solvent or without a solvent. Toluene, dioxane, methanol, dimethylformamide and dimethylsulfoxide are suitable solvents.
When the diazo lower alkane is used as the alkylating agent, the reaction is preferably carried out at a temperature of 0 to 40C, and especially 20 to 30C, in an inert solvent. Dioxane, tetrahydrofuran, methanol and mixtures thereof are suitable as the solvent. When the group R3 of the starting compound ~II) is a lower alkanoyl group, the reaction is preferably carried out in the presence of fluoroboric acid or silica gel.
When carrying out the above-mentioned alkylation reaction, it is particularly preferred to use the lower alkyl sulfate, lower alkyl sulfonate or lower alkyl halide as the alkylating agent when the group x2 of the ~ 5 ~3~
starting compound (II) is a hydrogen atom and the group R is the lower alkanoyl group; or alternatively it is particularly preferable to use the lower alkyl quaternary ammonium compound, lower alkyl sul~onium or sulfoxonium compound, lower alkyl selenonium compound or diazo lower alkane as the alkylating agent when both the groups x2 and R3 of the starting compound (II) are a hydrogen atom.
When the group x2 of the thus-obtained product is a protecting group, removal of the protecting group may be conducted in a conventional manner. For example, when the protecting group is an unsubstituted or substituted benzyloxycarbonyl or unsubstituted lower alkoxy carbonyl, the group may be readily removed by treating the compound with an acid e.g. hydrogen bromide, hydrogen chloride or trifluoroacetic acid in a solvent. When the protecting group is a substituted lower alkoxy carbonyl, the group may be removed by treatment with zinc in a solvent. On the other hand, when the protecting group is an unsubstituted or substituted phenyl lower alkyl, the group may be removed by first substituting it with a protecting group (e.g., benzyloxycarbonyl group) which is readily removable with an acid, and then treating the latter group in the same manner as mentioned above. Substitution of the unsubstituted or substituted phenyl lower alkyl with the benzyloxycarbonyl group is pre~erably carried out by treating the product (i.e., the compound in which the imino group is protected by the unsubstituted or substituted phenyl lower alkyl group) with benzyloxycarbonyl halide, e.g. benzyloxycarbonyl chloride, at a temperature between 50 and 130C in a solvent.
When R3 is the lower alkanoyl group, the protecting group and the lower alkanoyl group may be removed simul-taneously, or the protecting group may be removed without removal~ of the lower alkanoyl group. These reactions can be controlled by changing the reaction conditions, e.g.
the amount of the reaction agents, the reaction time and/or the reaction solvent used.
- 6 ~
If required, the compound (I) of the present invention thus obtained may be converted into its acid addition salts by treating it with an acid. Examples of the acid addition salts include inorganic acid addition salts e.g.
hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate or phosphate, organic acid addition salts e.g.
oxalate, maleate, fumarate or methanesulfonate, and so forth.
Since the above-mentioned reactions of the invention can be carried out without racemization, the compound (I) in an optically active form can be readily obtained by the use of an optically active isomer of the comp~nd (II) as the starting compound.
The starting compound (II) may be prepared, for lS example, by: reacting 3-(4-benzyloxyphenyl)glycidic acid methyl ester with 5-chloro-2-aminothiophenol to give 2-(4-benzyloxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzo-thiazepin-4(5H)-one or a salt thereof; condensing the product with a compound of the formula:
" , CH3 Y CH2CH2N (III) wherein Y is a halogen atom and x2 is the same as defined above, or a salt thereof, to give a compound of the formula:
Cl ~ ~ O-CH2 ~
OH (IV) I O CH
CH2CHzN /
~X 2 .
- 7 ~
wherein x2 is the same as defined above; removing the benzyl group Erom the compound (IV); and if required, converting the hydroxy gro~p of the thus-obtained product at the 3-position of the benzothiazepine ring into a lower alkanoyloxy group before or after removal of the benzyl ~roup.
The compound ~I) and the starting compound (II) can exist in the form of two diastereoisomers (e.g., cis and trans) or four optical isomers (e.g., (+)-cis, (-)-cis, (+)-trans, and (-)-trans) due to the two asymmetric carbon atoms involved therein, and all of these isomers and mixtures thereof are included within the scope o~ the invention. Among these isomers, however, the cis isomer o~ the compound (I) is pre~erred for medicinal use.
Presently preferred embodiments of the invention are described in detail in the following Examples which should not be construed as limiting.
Example 1 690 mg of (+)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2-(N,N-dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were dissolved in 20 ml of tetrahydrofuran. Sodium hydride (78 mg, 60% oily) was added thereto at room temperature and the mixture was stirred ~or 30 minutes at the same temperature. A
solution of 245 mg of dimethyl sul~ate in 10 ml of dimethylformamide was added thereto, and the mixture was stirred ~or 1 hour at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from a mixture of ethyl acetate and n-hexane. The product was 509 mg of (~)-cis-2-~4-methoxyphenyl)-3-hydroxy-5-12-(N,N-dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
M.p. 122-124C (decomp.) [~] D0 +144.6 (C=0.85, methanol) Examples 2 to 4 The corresponding starting compounds were treated in the same manner as described in Example 1 to gi~e the compounds shown in Table 1.
Table 1 Cl S ~ OH Cl S ~ OR' OR3 ~ ~ oR2 I O CH3 ~ O CH3 CHzCH2N / CHzCHzl~ /
(Il) \XZ ( I ) ~X' (R', X' and XZ- -CH3, R3= RZ) Ex. Compound ~I) Optlcal Properties No. R activity .
2: -H cis-(-) M.p. 121-123C (decomp.) : ~20 -142.70(c=l 04 _ D methanol) 3 -COCH3 ~ cis-~+) Maleate(recrystallized ~rom ~ etha.nol-ether) : : M.p. 158-160C
_ ~ ~ ( )2~75 4 (C=1.0,methanol) ~
4 -COCH3 cis-~ Hydrochloride :
:: ~ M~.p. 128-132C(decomp.) ; ~ : I : t~)D -93.3(C=0.872, ethanol) :
:
:
Example 5 A 210 mg amount of (~)-cis-2-(4-hydroxyphenyl)-3-acetoxy~5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 250 mg of potassium carbonate and 140 mg of dimethylsulfate were dissolved in 5 ml of methanol, and the solution ~7as stirred at room temperature overnight. Insoluble materials were filtered of, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (solvent; benzene : ethyl acetate = 4 : 1), converted into the maleate and recrystallized from a mixture of ethanol and ether. The product was 212 mg of (~)-cis-2-(4-methoxyphenyl)-3 acetoxy-5-[2-(N,N-dimethylamino)ethyl]-8-chloro-2,3-dihydo-1,5-benzothiazepin-4(5H)-one maleate.
The physico-chemical properties of this product were identical to those of the product prepared in Example 3.
Example 6 (1) (-)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin~4(5H)-one was treated in ~he same manner as described in Example 1 to give (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Perl_hlorate (recrystallized from ethanol) M.p. 161-163C (decomp.) ~] D -76.4 (C=0.589, methanol) (2) 4.3 g of the product obtained in paragraph (1) were dissolved in 50 ml of benzene and reflux~d. A solution of 4.55 g of benzyloxycarbonyl chloride in 10 ml of benzene was added dropwise thereto for 15 minutes. The solution was refluxed for 1 hour, cooled to room temperature, and evaporated to remove the solvent. To the residue were added 30 ml of ethanol and 50 ml of 5% aqueous sodium hydroxide, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water and extracted with chloroform. The extract was washed with water, dried and evaporated to remove the solvent.
The product was 4.79 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
IRv CHC13 (cm~l): 3510, 1695, 1660 [~] D -133.3 (C=0.582, methanol) (3) 1.07 g of the product obtained in paragraph (2) were dissolved in 2 ml of benzene, and 1.7 ml of a 25%
hydrogen bromide-acetic acid solution were added thereto.
The mixture was stirred for 2 hours at room temperature.
Ether was added thereto, and the precipitates were collected by filtration and washed with ether. To the precipitates were added water and benzene, and the mixture was made alkaline with potassium carbonate. The benzene layer was washed with water, dried, and evapora~ed to remove the solvent. Ether was added to the residue. The precipitates were collected by filtration, and recrystal-lized from a mixture of ethyl acetate and n-hexane. The product was 0.47 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
M.p. 142-145C
[~] D -147.7 (C=0.814, chloroform) Fumarate (recrystallized from ethanol) M.p. 164-167C(decomp.) Examples 7 to 9 (1) The corresponding starting compounds were treated in the same manner as described in Example 6-(1) to give the compounds shown in Table 2.
Table 2 Cl : ~30~1 Cl ~OR~
\~S~ ~S
O R 3~ O R ~
O ~CH~ - - > l \o CH3 CH2:CHzN \ CHzCH z N <
( V ) ~R~= -CH~, ~XZ= -CHzCt,Hs) `' ~ :
.
~ -- ~- - - ---~
Ex. Compound (V) Optical Properties No. R3 activity . _ _ _ . _ _ 7 -H cis-(+) Perchlora~e(recrystallized from ethanol) M.p. 161-163C(decomp.) methanol) _ ~ . , 8 -COCH3 cis-(-) Oxalate(recrystallized from ethanol) M.p. 192-194C(decomp.) [~] D -96.5(C=1.0, dimethylformamide) .~ _ . ~ _ .
9 -COCH3 cis-(+) Oxalate(recrystallized from ethanol) M.p~ 191-194C (decomp.) [a] D ~96.8(C=0.73, _ _ dimethylformamide) (2) The products (V~ obtained above were treated in the same manner~as described in Example 6-(2) to give the compounds shown~in Table 3.
~ Table 3 Cl ~ ~ OR' - \~ S ~ \=/:
N :~
b: ~C It 3 c N 2 c a ~ly \CH
(V-a) ~S
N
CH,CHzN
(Y-b) , ~ ~
( R; ~ P ~ - C II 3~
`: :
- 12 ~ 3~
,~ . . .
Ex. Compound (V-b) Optical Properties No. R3 activity ... _ .....
7 -H cis--(+) [~,] 20 ~132.6 (C=0.550, methanol ) 8 -COCH3*) cis- (-) IR~mCaHxcl3 (cm~l) :1740,1685 [c~ ] 20 -115. 4 (C=l . O, . D methanol) 9 -COCH3 * ) c i s- (+ ) [cl ] 20 +115 . 5 (C= 1- O
D methanol) ~note: *): After th~ ~ reaction, the residue was not treated with ethanol-aqueous sodium hydroxide.
(3) The products (V-b) obtained above were treated in the same manner as described in Example 6- (3) to give the compounds shown in Table 4.
: Table 4 Cl~ ~ ,~OR':
\~ ~OR3 N ~\
CHzCH~N /
~\C O O C H, ~
C i ~ O R ' o R 2 > I O CH3 C H ~ C R ~ N <
R~ C N 3, ~ R Z = - R, R ' ~ - H o r - C O C H 3 ) : :
.
:
- 1 3 - ~' .3~
.
Ex . Compound (I-a) ._._ _ . . . , .. __ No. Optical activity Properties . . _._ ._ _ 7 cis-(+) Hydrochloride 1/2 hydrate (recrystallized from the mixture of ethanol and ether) M.p. 137-140C
[a] 20 +8304tC=0.415,methanol) . _ 8 cis-(-) identical with those of the product prepared in Example 6-(3) . ..
9 cis-(+) identical with those of the product prepared in Example 7-~3) .
Example 10 450 mg of (-)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2-~N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were dissolved in 20 ml of S toIuene, and a solution of 490 mg of benzyloxycarbonyl chloride in 10 ml of toluene was added thereto at 80C.
The mixture was stirred at 80C for 5 hours. After the reaction, the solvent was distilled off. To the residue were added 10 ml of 5% aqueous sodium hydroxide and 10 ml of methanol, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was evaporated off. Then the residue was purified by silica~gel column chromatography (solvent;
chloroform : methanol = 9 : 1) to give 410 mg of (-)-cis-2-(4-hydroxyphenyl)-3-hydroxy-S-~2-(N-benzyloxycarbonyl-N-methylamino)~ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-415H)~-one.
: :
- 14 - ~ ~q~
t2) A mixture of 410 mg of the product obtained in paragraph (1), 340 mg of potassium carbonate, 170 mg o~
methyl iodide and 10 ml of methanol was stirred at room temperature for 40 hours. After the reaction, the mixture was evaporated to remove the solvent, and the residue was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium hydroxide and water, dried, and evaporated to remove the solvent. The product was 315 mg of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy 5-[2-(N-benzyloxy-carbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
The physico-chemical properties of this product were identical to those of the product prepared in Example 6-(2)-(3) The product obtained in paragraph (2) was treated in the same manner as described in Example 6-(3), whereby (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino) ethyl]-8~chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was obtained.
Example 11 (1) (-)-cis-2-(4-hydroxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was treated in the same manner as described in Example 8-(2) to give (-)-cis-2-(4-hydroxy-phenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N~methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
[a] D -106.0(C=O.S0, chloro~orm) (2) The product obtained in paragraph (1) was treated in the same manner as described in Example 10-(2) to give (-)-cis-2-(4-methoxyphenyl)-3-acetoxy~5-[2-(N-benzyloxy-carbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
(3) 37.5 g of the product obtained in paragraph (2) and 75 ml of 25% hydrogen bromide-acetic acid and 95 ml of dichloromethane were mixed under ice-cooling, and the mixture was stirred at room temperature for 3 hours.
.
After the reaction, the dichloromethane was distilled off, and ether was added to the residue. After the precip-itates were washed with ether, the precipitates were dissolved in water. The solution was neutralized wi'ch potassium carbonate, and extracted with ether. The extract was washed with water, dried and evaporated to remove the solvent. The residue was conver'ced into the oxalate, and recrystallized from methanol. The product was 18.7 9 of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-~2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5~benzothiaze-pin-4(5H)-one oxalate.
M.p. 174--176C
[~] 20 -74.2(C=0.814, methanol) Example 12 645 mg of trimethylammonium tosylate were added to sodium methoxide (prepared from 46 mg of sodium metal and 4.5 ml of methanol), and the mixture was stirred at room temperature for 3 hours. Insoluble materials were filtered off, and the filtrate was added to 20 ml of a toluene solution containing 570 mg of (-)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2- (N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. After the methanol was distilled off, the solution was refluxed for 2 hours.
After the reaction, the mixture was evaporated ~o remove the solvent. The residue was purified by silica gel column chromatography (solvent: chloroform: ethanol =
95: 5) and recrystallized from the mixture of ethyl acetate and n-hexane. The product was 275 mg of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2- (N-methylamino)ethyl]-8-chloro-2~3-dihydro-1,5-benæothiazepin-4(5H)-one.
The physico-chemical properties of this product were identical to those of the product prepared in Example 6-(3) Preparation of Starting Compounds Preparation 1 (1~ A mixture of (+)-trans-3-(4-benzyloxyphenyl) glycidic acid methyl ester and 5-chloro-2~aminothiophenol was heated at 160C for 16 hours. Then (S)-N-(2-naphtha-lenesulfonyl)pyrrolidine-2-carbonyl chloride and pyridine were added to the reaction solution~ and the solution was stirred. After the reaction, the product was separated by silica gel column chromatography (solvent; benzene : ethyl acetate = 4 : 1) into the (+)-isomer and (-)-isomer thereof. After the separation, potassium carbonate, water and methanol were added to each of the isomers, and the mixtures were stirred at room temperature overnight.
Recrystallization of each product from ethyl acetate gave (+)- and (-)-isomers of cis-2-(4-benzyloxyphenyl)-3-hydroxy -8-chloro-2,3-dihydro-1,5-benzothiazepin-4-(5H)-one 1/5 ethyl acetate, respectively. (~)-isomer 1/5 ethyl acetate:
[~] 20 -74.2(C=l~00, dimethylformamide) (-)-isomer 1/5 ethyl acetate:
[~] D -75.0(C=l.00, dimethylformamide) (2) A mixture of (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4-(5H)-one, 2-(N-benzyl-N-methylamino)ethyl chloride hydrochloride, potassium carbonate, acetone, ethyl acetate and water was refluxed. After the reaction, insoluble materials were filtered off, and the filtrate was evaporated to remove the solvent. The residue was converted into oxalate and recrystallized from a mixture of methanol and ether to give (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyll-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate.
M.p. 108-115C
[ ] D +85.8(C=l.00, methar.ol) (3) The product obtained in paragraph (2) (free base) was dissolved in pyridine, a solution of acetyl chloride in dichloromethane was added thereto, and the mixture was stirred. After the reaction, the mixture was evaporated to remove the solvent, and the residue was dissolved in ethyl acetate. The solution was washed with water J
:: ~ M~.p. 128-132C(decomp.) ; ~ : I : t~)D -93.3(C=0.872, ethanol) :
:
:
Example 5 A 210 mg amount of (~)-cis-2-(4-hydroxyphenyl)-3-acetoxy~5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 250 mg of potassium carbonate and 140 mg of dimethylsulfate were dissolved in 5 ml of methanol, and the solution ~7as stirred at room temperature overnight. Insoluble materials were filtered of, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (solvent; benzene : ethyl acetate = 4 : 1), converted into the maleate and recrystallized from a mixture of ethanol and ether. The product was 212 mg of (~)-cis-2-(4-methoxyphenyl)-3 acetoxy-5-[2-(N,N-dimethylamino)ethyl]-8-chloro-2,3-dihydo-1,5-benzothiazepin-4(5H)-one maleate.
The physico-chemical properties of this product were identical to those of the product prepared in Example 3.
Example 6 (1) (-)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin~4(5H)-one was treated in ~he same manner as described in Example 1 to give (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Perl_hlorate (recrystallized from ethanol) M.p. 161-163C (decomp.) ~] D -76.4 (C=0.589, methanol) (2) 4.3 g of the product obtained in paragraph (1) were dissolved in 50 ml of benzene and reflux~d. A solution of 4.55 g of benzyloxycarbonyl chloride in 10 ml of benzene was added dropwise thereto for 15 minutes. The solution was refluxed for 1 hour, cooled to room temperature, and evaporated to remove the solvent. To the residue were added 30 ml of ethanol and 50 ml of 5% aqueous sodium hydroxide, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water and extracted with chloroform. The extract was washed with water, dried and evaporated to remove the solvent.
The product was 4.79 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
IRv CHC13 (cm~l): 3510, 1695, 1660 [~] D -133.3 (C=0.582, methanol) (3) 1.07 g of the product obtained in paragraph (2) were dissolved in 2 ml of benzene, and 1.7 ml of a 25%
hydrogen bromide-acetic acid solution were added thereto.
The mixture was stirred for 2 hours at room temperature.
Ether was added thereto, and the precipitates were collected by filtration and washed with ether. To the precipitates were added water and benzene, and the mixture was made alkaline with potassium carbonate. The benzene layer was washed with water, dried, and evapora~ed to remove the solvent. Ether was added to the residue. The precipitates were collected by filtration, and recrystal-lized from a mixture of ethyl acetate and n-hexane. The product was 0.47 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
M.p. 142-145C
[~] D -147.7 (C=0.814, chloroform) Fumarate (recrystallized from ethanol) M.p. 164-167C(decomp.) Examples 7 to 9 (1) The corresponding starting compounds were treated in the same manner as described in Example 6-(1) to give the compounds shown in Table 2.
Table 2 Cl : ~30~1 Cl ~OR~
\~S~ ~S
O R 3~ O R ~
O ~CH~ - - > l \o CH3 CH2:CHzN \ CHzCH z N <
( V ) ~R~= -CH~, ~XZ= -CHzCt,Hs) `' ~ :
.
~ -- ~- - - ---~
Ex. Compound (V) Optical Properties No. R3 activity . _ _ _ . _ _ 7 -H cis-(+) Perchlora~e(recrystallized from ethanol) M.p. 161-163C(decomp.) methanol) _ ~ . , 8 -COCH3 cis-(-) Oxalate(recrystallized from ethanol) M.p. 192-194C(decomp.) [~] D -96.5(C=1.0, dimethylformamide) .~ _ . ~ _ .
9 -COCH3 cis-(+) Oxalate(recrystallized from ethanol) M.p~ 191-194C (decomp.) [a] D ~96.8(C=0.73, _ _ dimethylformamide) (2) The products (V~ obtained above were treated in the same manner~as described in Example 6-(2) to give the compounds shown~in Table 3.
~ Table 3 Cl ~ ~ OR' - \~ S ~ \=/:
N :~
b: ~C It 3 c N 2 c a ~ly \CH
(V-a) ~S
N
CH,CHzN
(Y-b) , ~ ~
( R; ~ P ~ - C II 3~
`: :
- 12 ~ 3~
,~ . . .
Ex. Compound (V-b) Optical Properties No. R3 activity ... _ .....
7 -H cis--(+) [~,] 20 ~132.6 (C=0.550, methanol ) 8 -COCH3*) cis- (-) IR~mCaHxcl3 (cm~l) :1740,1685 [c~ ] 20 -115. 4 (C=l . O, . D methanol) 9 -COCH3 * ) c i s- (+ ) [cl ] 20 +115 . 5 (C= 1- O
D methanol) ~note: *): After th~ ~ reaction, the residue was not treated with ethanol-aqueous sodium hydroxide.
(3) The products (V-b) obtained above were treated in the same manner as described in Example 6- (3) to give the compounds shown in Table 4.
: Table 4 Cl~ ~ ,~OR':
\~ ~OR3 N ~\
CHzCH~N /
~\C O O C H, ~
C i ~ O R ' o R 2 > I O CH3 C H ~ C R ~ N <
R~ C N 3, ~ R Z = - R, R ' ~ - H o r - C O C H 3 ) : :
.
:
- 1 3 - ~' .3~
.
Ex . Compound (I-a) ._._ _ . . . , .. __ No. Optical activity Properties . . _._ ._ _ 7 cis-(+) Hydrochloride 1/2 hydrate (recrystallized from the mixture of ethanol and ether) M.p. 137-140C
[a] 20 +8304tC=0.415,methanol) . _ 8 cis-(-) identical with those of the product prepared in Example 6-(3) . ..
9 cis-(+) identical with those of the product prepared in Example 7-~3) .
Example 10 450 mg of (-)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2-~N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were dissolved in 20 ml of S toIuene, and a solution of 490 mg of benzyloxycarbonyl chloride in 10 ml of toluene was added thereto at 80C.
The mixture was stirred at 80C for 5 hours. After the reaction, the solvent was distilled off. To the residue were added 10 ml of 5% aqueous sodium hydroxide and 10 ml of methanol, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was evaporated off. Then the residue was purified by silica~gel column chromatography (solvent;
chloroform : methanol = 9 : 1) to give 410 mg of (-)-cis-2-(4-hydroxyphenyl)-3-hydroxy-S-~2-(N-benzyloxycarbonyl-N-methylamino)~ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-415H)~-one.
: :
- 14 - ~ ~q~
t2) A mixture of 410 mg of the product obtained in paragraph (1), 340 mg of potassium carbonate, 170 mg o~
methyl iodide and 10 ml of methanol was stirred at room temperature for 40 hours. After the reaction, the mixture was evaporated to remove the solvent, and the residue was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium hydroxide and water, dried, and evaporated to remove the solvent. The product was 315 mg of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy 5-[2-(N-benzyloxy-carbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
The physico-chemical properties of this product were identical to those of the product prepared in Example 6-(2)-(3) The product obtained in paragraph (2) was treated in the same manner as described in Example 6-(3), whereby (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino) ethyl]-8~chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was obtained.
Example 11 (1) (-)-cis-2-(4-hydroxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was treated in the same manner as described in Example 8-(2) to give (-)-cis-2-(4-hydroxy-phenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N~methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
[a] D -106.0(C=O.S0, chloro~orm) (2) The product obtained in paragraph (1) was treated in the same manner as described in Example 10-(2) to give (-)-cis-2-(4-methoxyphenyl)-3-acetoxy~5-[2-(N-benzyloxy-carbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
(3) 37.5 g of the product obtained in paragraph (2) and 75 ml of 25% hydrogen bromide-acetic acid and 95 ml of dichloromethane were mixed under ice-cooling, and the mixture was stirred at room temperature for 3 hours.
.
After the reaction, the dichloromethane was distilled off, and ether was added to the residue. After the precip-itates were washed with ether, the precipitates were dissolved in water. The solution was neutralized wi'ch potassium carbonate, and extracted with ether. The extract was washed with water, dried and evaporated to remove the solvent. The residue was conver'ced into the oxalate, and recrystallized from methanol. The product was 18.7 9 of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-~2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5~benzothiaze-pin-4(5H)-one oxalate.
M.p. 174--176C
[~] 20 -74.2(C=0.814, methanol) Example 12 645 mg of trimethylammonium tosylate were added to sodium methoxide (prepared from 46 mg of sodium metal and 4.5 ml of methanol), and the mixture was stirred at room temperature for 3 hours. Insoluble materials were filtered off, and the filtrate was added to 20 ml of a toluene solution containing 570 mg of (-)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2- (N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. After the methanol was distilled off, the solution was refluxed for 2 hours.
After the reaction, the mixture was evaporated ~o remove the solvent. The residue was purified by silica gel column chromatography (solvent: chloroform: ethanol =
95: 5) and recrystallized from the mixture of ethyl acetate and n-hexane. The product was 275 mg of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2- (N-methylamino)ethyl]-8-chloro-2~3-dihydro-1,5-benæothiazepin-4(5H)-one.
The physico-chemical properties of this product were identical to those of the product prepared in Example 6-(3) Preparation of Starting Compounds Preparation 1 (1~ A mixture of (+)-trans-3-(4-benzyloxyphenyl) glycidic acid methyl ester and 5-chloro-2~aminothiophenol was heated at 160C for 16 hours. Then (S)-N-(2-naphtha-lenesulfonyl)pyrrolidine-2-carbonyl chloride and pyridine were added to the reaction solution~ and the solution was stirred. After the reaction, the product was separated by silica gel column chromatography (solvent; benzene : ethyl acetate = 4 : 1) into the (+)-isomer and (-)-isomer thereof. After the separation, potassium carbonate, water and methanol were added to each of the isomers, and the mixtures were stirred at room temperature overnight.
Recrystallization of each product from ethyl acetate gave (+)- and (-)-isomers of cis-2-(4-benzyloxyphenyl)-3-hydroxy -8-chloro-2,3-dihydro-1,5-benzothiazepin-4-(5H)-one 1/5 ethyl acetate, respectively. (~)-isomer 1/5 ethyl acetate:
[~] 20 -74.2(C=l~00, dimethylformamide) (-)-isomer 1/5 ethyl acetate:
[~] D -75.0(C=l.00, dimethylformamide) (2) A mixture of (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4-(5H)-one, 2-(N-benzyl-N-methylamino)ethyl chloride hydrochloride, potassium carbonate, acetone, ethyl acetate and water was refluxed. After the reaction, insoluble materials were filtered off, and the filtrate was evaporated to remove the solvent. The residue was converted into oxalate and recrystallized from a mixture of methanol and ether to give (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyll-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate.
M.p. 108-115C
[ ] D +85.8(C=l.00, methar.ol) (3) The product obtained in paragraph (2) (free base) was dissolved in pyridine, a solution of acetyl chloride in dichloromethane was added thereto, and the mixture was stirred. After the reaction, the mixture was evaporated to remove the solvent, and the residue was dissolved in ethyl acetate. The solution was washed with water J
5% aqueous sodium bicarbonate and water, successively.
Then, the solution was dried and evaporated to remove the solvent. The residue was converted into the oxalate, and recrystalIized from the mixture of methanol and ether.
The product was (+)-cis-2-(4-benzyloxyphenyl)-3-acetoxy-5-[2- (N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate.
M.p. 173-175C
[ ] D +78.4(C=l.00, methanol) (-)-cis isomer oxalate M.p. 172-175C
(4) The product obtained in paragraph (3) (free base) was dissolved in toluene, and a solution of benzyloxy-20 carbonyl chloride in toluene was added dropwise thereto.The mixture was stirred under heating. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform:
ethyl acetate = 95: 5), and recrystallized from a mixtu~e 25 of ethyl acetate and n-hexane. The product was (+)-cis-2- (4-benzyloxyphenyl)-3-acetoxy-5-[2- (N-benzyloxycarbonyl-N-me'chylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin -4(5H)-one.
[ ] D +79.0(C=l.00, chloroform) 30 (-)-isomer [c~] 20 -79.2(C=l.00, chloroform) (5) The product obtained in paragraph (4~ ~7as dissolved in e~hyl acetate, and thereto was added 25%
hydrogen bromide-acetic acid under cooling. ~fter the reaction, the solvent was distilled off. The residue ~as washed with ether, neutralized with conc. aqueous ammonia to give the corresponding free base, and extracted with chloroform. The extract was washed with water, dried and evaporated to remove the solvent. The residue was purified by silica gel column chromatography and converted into the oxalate. The product was (+)-cis-2-(4-hydroxyphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate.
.p. 186-189C
[a] ~ +81.2(C=0.50, methanol) (-)-cis-isomer M.p. 187-189C
[~] D -81.6(C=0.50, methanol) Preparation 2 (1) (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was treated in the same manner as described in Preparation 1-(4) to give (~)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
M.p. 94-96C
[~] 20 ~126.0(C=l. 00, chloroform) (-)-cis-isomer M.p. 93-95C
la] D0 -125.6(C=l.OOj chloroform) (2) The product obtained in paragraph (1) was treated in the same manner as described in Preparation 1-(5). The free base obtained was converted to the corresponding 2-(4-hydroxy-benzoyl)benzoate, and recrystallized from aqueous ethanol to give (+)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2~(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 2-(4-hydroxybenzoyl) benzoate 3/2 hydrate.
M.p. 124-127C
[~j] D0 ~198.1(C=0.120, methanol) (-)-cis-isomer 2-(4-hydroxy-benzoyl)benzoate 3/2 hydrate M.p. 124-127C
[~i] D -197.5(C=0.120, methanol) Preparation 3 lS (1) (+)cis-2-(4-benzyloxyphenyl)-3-hydroxy-a-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 2-(N,N-dimethylamino)ethyl chloride hydrochloride were treated in the same manner as described in Preparation 1-(2) to give (~)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-[2-(N,N-dimethyl-amino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (SH)-one oxalate.
M.p. 148-151C (decomp.) [ ] D ~94.0(C=l.00, methanol~
(-)-cis-isomer oxalate M.p. 149-152C (decomp.) [ ] D -94.2(C=l.00, methanol) (2) A mixture of the product obtained in paragraph (1) (free base), acetic anhydride and pyridine was stirred under heating. After the reaction,ithe solvent was dis-tilled off, and the residue was converted into the oxalate,and recrystallized from a mixture of methanol and ether.
The product was (+)cis-2-(4-benzyloxyphenyl~-3-acetoxy-5-[2- (N,N-dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1/2 oxalate.
M.p. 168-172C tdecomP ) [a ] 20 ~78.4(C=l.00, methanol) (-)-cis-isomer 1/2 oxalate M.p. 168-171C (decomp.) [~] D -78.8(C=l.00, methanol) (3) The product obtained in paragraph (2) (free base) was dissolved in acetic acid, and 25~6 hydrogen bromide-acetic acid was added thereto under cooling and the mixture was stirred. After the reaction, the solvent was distilled off. the residue was washed with ether, neutralized with conc. aqueous ammonia to give the free base, and extracted with chloroform. The extract was washed with water, dried, and evaporated to remove the solvent. The residue was converted into the oxalate and recrystallized from ethanol. The product was (~)cis~2~
(4-hydroxyphenyl)-3-acetoxy-5-[2- (N,N-dimethylamino)ethyl~-~ 8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate 1 hydrate.
M~p. 142-149C
[] 20 ~ +79.2(C=O.S0, methanol) ois-isomer oxala~e 1 hydrate M.p. 143-149C
[a] 20 -78.~3(C=O.S0, methanol) .
Preparations 4 to 6 The corresponding starting compounds are treated in the ~same~manner~ as described in Preparation 3-(3~ to give the compounds shown in Table 5.
, Table 5 Cl ~30-CH
k~ S---, N ~
CHzCHzN <
(IV) X2 Cl ~OH
\,~S~ .
: : : : CHzCHzN /
~ ~ . ( Il ) \X2 ~ ~ :
: : : ::
: ~ .
,( Pr. Compo~ Ind ~II) Optical Properties No. R3 x2 activity 2-(4-hydroxybenzoyl)benzoat~
(recrystallized from a ciS-(~) mixture o acetone and isopropyl ether) M.p. 165-170C (dec.) [~]D +79.8~C=1.00,methanol) 4 -H -CH3 _ 2-(4-hydroxybenzoyl)benzoate (recrystallized from a cis-(-) mixture of acetone and isopropyl ether) M.p. 166-170C (dec.) ~ a] 2-80.1(C=1.00lmethanol) _ Oxalate (recrystallized from . cis-(+) a mixture of ethanol and ether) M.p. 130-135C (dec.) a] D+97.6(c=0.50,methanol) 5 -H -C~2C6H5 Oxalate (recrystallized from cis-(-) a mixture of ethanol and ether) : M.p. 130-135C (dec.) . ~ [a]D -97.5(C=0.50,methanol) _ : _ 1/2 oxalate 1 hydrate . (recrystallized from a : mixture of acetone and : ciS-(+) ether) M.p 103-113C (dec.) : . ~ [a]D +78.4(C=1.00,methanol) 6 -COCH3 CH2 6 5 _ _ .
1/2 oxalate 1 hydrate : (recrystallized from a cis-(-) mixture of acetone and : : ether) : ~ M.p. 103-114C (dec.) _ _ ~ ~ ~ [~]D -78.8(C=1.00,methanol)
Then, the solution was dried and evaporated to remove the solvent. The residue was converted into the oxalate, and recrystalIized from the mixture of methanol and ether.
The product was (+)-cis-2-(4-benzyloxyphenyl)-3-acetoxy-5-[2- (N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate.
M.p. 173-175C
[ ] D +78.4(C=l.00, methanol) (-)-cis isomer oxalate M.p. 172-175C
(4) The product obtained in paragraph (3) (free base) was dissolved in toluene, and a solution of benzyloxy-20 carbonyl chloride in toluene was added dropwise thereto.The mixture was stirred under heating. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform:
ethyl acetate = 95: 5), and recrystallized from a mixtu~e 25 of ethyl acetate and n-hexane. The product was (+)-cis-2- (4-benzyloxyphenyl)-3-acetoxy-5-[2- (N-benzyloxycarbonyl-N-me'chylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin -4(5H)-one.
[ ] D +79.0(C=l.00, chloroform) 30 (-)-isomer [c~] 20 -79.2(C=l.00, chloroform) (5) The product obtained in paragraph (4~ ~7as dissolved in e~hyl acetate, and thereto was added 25%
hydrogen bromide-acetic acid under cooling. ~fter the reaction, the solvent was distilled off. The residue ~as washed with ether, neutralized with conc. aqueous ammonia to give the corresponding free base, and extracted with chloroform. The extract was washed with water, dried and evaporated to remove the solvent. The residue was purified by silica gel column chromatography and converted into the oxalate. The product was (+)-cis-2-(4-hydroxyphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate.
.p. 186-189C
[a] ~ +81.2(C=0.50, methanol) (-)-cis-isomer M.p. 187-189C
[~] D -81.6(C=0.50, methanol) Preparation 2 (1) (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was treated in the same manner as described in Preparation 1-(4) to give (~)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
M.p. 94-96C
[~] 20 ~126.0(C=l. 00, chloroform) (-)-cis-isomer M.p. 93-95C
la] D0 -125.6(C=l.OOj chloroform) (2) The product obtained in paragraph (1) was treated in the same manner as described in Preparation 1-(5). The free base obtained was converted to the corresponding 2-(4-hydroxy-benzoyl)benzoate, and recrystallized from aqueous ethanol to give (+)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-[2~(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 2-(4-hydroxybenzoyl) benzoate 3/2 hydrate.
M.p. 124-127C
[~j] D0 ~198.1(C=0.120, methanol) (-)-cis-isomer 2-(4-hydroxy-benzoyl)benzoate 3/2 hydrate M.p. 124-127C
[~i] D -197.5(C=0.120, methanol) Preparation 3 lS (1) (+)cis-2-(4-benzyloxyphenyl)-3-hydroxy-a-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 2-(N,N-dimethylamino)ethyl chloride hydrochloride were treated in the same manner as described in Preparation 1-(2) to give (~)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-[2-(N,N-dimethyl-amino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (SH)-one oxalate.
M.p. 148-151C (decomp.) [ ] D ~94.0(C=l.00, methanol~
(-)-cis-isomer oxalate M.p. 149-152C (decomp.) [ ] D -94.2(C=l.00, methanol) (2) A mixture of the product obtained in paragraph (1) (free base), acetic anhydride and pyridine was stirred under heating. After the reaction,ithe solvent was dis-tilled off, and the residue was converted into the oxalate,and recrystallized from a mixture of methanol and ether.
The product was (+)cis-2-(4-benzyloxyphenyl~-3-acetoxy-5-[2- (N,N-dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1/2 oxalate.
M.p. 168-172C tdecomP ) [a ] 20 ~78.4(C=l.00, methanol) (-)-cis-isomer 1/2 oxalate M.p. 168-171C (decomp.) [~] D -78.8(C=l.00, methanol) (3) The product obtained in paragraph (2) (free base) was dissolved in acetic acid, and 25~6 hydrogen bromide-acetic acid was added thereto under cooling and the mixture was stirred. After the reaction, the solvent was distilled off. the residue was washed with ether, neutralized with conc. aqueous ammonia to give the free base, and extracted with chloroform. The extract was washed with water, dried, and evaporated to remove the solvent. The residue was converted into the oxalate and recrystallized from ethanol. The product was (~)cis~2~
(4-hydroxyphenyl)-3-acetoxy-5-[2- (N,N-dimethylamino)ethyl~-~ 8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate 1 hydrate.
M~p. 142-149C
[] 20 ~ +79.2(C=O.S0, methanol) ois-isomer oxala~e 1 hydrate M.p. 143-149C
[a] 20 -78.~3(C=O.S0, methanol) .
Preparations 4 to 6 The corresponding starting compounds are treated in the ~same~manner~ as described in Preparation 3-(3~ to give the compounds shown in Table 5.
, Table 5 Cl ~30-CH
k~ S---, N ~
CHzCHzN <
(IV) X2 Cl ~OH
\,~S~ .
: : : : CHzCHzN /
~ ~ . ( Il ) \X2 ~ ~ :
: : : ::
: ~ .
,( Pr. Compo~ Ind ~II) Optical Properties No. R3 x2 activity 2-(4-hydroxybenzoyl)benzoat~
(recrystallized from a ciS-(~) mixture o acetone and isopropyl ether) M.p. 165-170C (dec.) [~]D +79.8~C=1.00,methanol) 4 -H -CH3 _ 2-(4-hydroxybenzoyl)benzoate (recrystallized from a cis-(-) mixture of acetone and isopropyl ether) M.p. 166-170C (dec.) ~ a] 2-80.1(C=1.00lmethanol) _ Oxalate (recrystallized from . cis-(+) a mixture of ethanol and ether) M.p. 130-135C (dec.) a] D+97.6(c=0.50,methanol) 5 -H -C~2C6H5 Oxalate (recrystallized from cis-(-) a mixture of ethanol and ether) : M.p. 130-135C (dec.) . ~ [a]D -97.5(C=0.50,methanol) _ : _ 1/2 oxalate 1 hydrate . (recrystallized from a : mixture of acetone and : ciS-(+) ether) M.p 103-113C (dec.) : . ~ [a]D +78.4(C=1.00,methanol) 6 -COCH3 CH2 6 5 _ _ .
1/2 oxalate 1 hydrate : (recrystallized from a cis-(-) mixture of acetone and : : ether) : ~ M.p. 103-114C (dec.) _ _ ~ ~ ~ [~]D -78.8(C=1.00,methanol)
Claims (8)
1. A process for preparing a 1,5-benzothiazepine derivative of the formula:
(I) wherein R1 is a lower alkyl group, R2 is a hydrogen atom or a lower alkanoyl group, and X1 is a hydrogen atom or a lower alkyl group, or a salt thereof; which process comprises:
i) alkylating a compound of the formula:
(n) wherein R3 is a hydrogen atom or a lower alkanoyl group, and X2 is a hydrogen atom, a lower alkyl group, or a protecting group;
ii) when X2 is a protecting group, removing said protecting group therefrom;
iii) when R3 is a lower alkanoyl group, optionally removing said lower alkanoyl therefrom; and iv) if required, further converting the product into a salt thereof.
(I) wherein R1 is a lower alkyl group, R2 is a hydrogen atom or a lower alkanoyl group, and X1 is a hydrogen atom or a lower alkyl group, or a salt thereof; which process comprises:
i) alkylating a compound of the formula:
(n) wherein R3 is a hydrogen atom or a lower alkanoyl group, and X2 is a hydrogen atom, a lower alkyl group, or a protecting group;
ii) when X2 is a protecting group, removing said protecting group therefrom;
iii) when R3 is a lower alkanoyl group, optionally removing said lower alkanoyl therefrom; and iv) if required, further converting the product into a salt thereof.
2. A process according to Claim 1 wherein the alkylation is conducted by treating the compound (II) with a lower alkanol at a temperature of 0 to 40°C in the presence of a dehydrating agent.
3. A process according to Claim 1 wherein the alkylation is conducted by treating the compound (II) with a lower alkyl sulfate, a lower alkyl sulfonate or a lower alkyl halide at a temperature between 0°C and the refluxing temperature in the presence of a base in an inert solvent.
4. A process according to Claim 1 wherein the alkylation is conducted by treating the compound (II) with a lower alkyl quaternary ammonium compound, a lower alkyl sulfonium or sulfoxonium compound or a lower alkyl selenonium compound at a temperature between 10°C and the refluxing temperature.
5. A process according to Claim 1 wherein the alkylation is conducted by treating the compound (II) with a diazo lower alkane at a temperature of 0 to 40°C in an inert solvent.
6. A process according to Claim 5 wherein the treatment temperature is in the range of 20 to 30°C.
7. Use of a 1,5-benzothiazepine derivative of the formula (I) as defined in Claim 1 wherein X' is a lower alkyl group for the treatment, amelioration and prophylaxis of hypertension, cerebral diseases and heart diseases.
8. Use of a 1,5-benzothiazepine derivative of the formula (I) as defined in Claim 1 wherein X' is a hydrogen atom for the treatment, amelioration and prophylaxis of thrombotic diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61001845A JPS62161776A (en) | 1986-01-07 | 1986-01-07 | Production of 1,5-benzothiazepine derivative |
| JP1845/1986 | 1986-01-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1291134C true CA1291134C (en) | 1991-10-22 |
Family
ID=11512884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000526793A Expired - Fee Related CA1291134C (en) | 1986-01-07 | 1987-01-06 | Process for preparing 1,5-benzothiazepine derivatives |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS62161776A (en) |
| KR (1) | KR910002879B1 (en) |
| CN (1) | CN1030388C (en) |
| AT (1) | AT394367B (en) |
| BG (1) | BG46747A3 (en) |
| CA (1) | CA1291134C (en) |
| DD (1) | DD257426A5 (en) |
| ES (1) | ES2003642A6 (en) |
| FI (1) | FI865343A (en) |
| HU (1) | HU198031B (en) |
| IE (1) | IE59359B1 (en) |
| IL (1) | IL81039A (en) |
| PT (1) | PT84036B (en) |
| SU (1) | SU1544187A3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2736671C1 (en) * | 2020-05-19 | 2020-11-19 | федеральное государственное бюджетное образовательное учреждение высшего образования «Санкт-Петербургский горный университет» | Blocking hydrophobic-emulsion solution with marble chips |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5580867A (en) * | 1994-09-09 | 1996-12-03 | Universite De Montreal | Myocardial protection during ischemia and reperfusion |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57169476A (en) * | 1981-04-13 | 1982-10-19 | Hamari Yakuhin Kogyo Kk | Novel preparation of benzothiazepine derivative |
| JPS57175182A (en) * | 1981-04-22 | 1982-10-28 | Hamari Yakuhin Kogyo Kk | Novel preparation of benzothiazepin derivative |
| JPS58113186A (en) * | 1981-12-28 | 1983-07-05 | Hamari Yakuhin Kogyo Kk | Novel preparation of benzothiazepin derivative |
| JPS58116476A (en) * | 1981-12-29 | 1983-07-11 | Hamari Yakuhin Kogyo Kk | Novel preparation of benzothiazepine derivative |
| US4567175A (en) * | 1983-06-03 | 1986-01-28 | Tanabe Seiyaku Co., Ltd. | 8-Chloro-1,5-benzothiazepine derivatives |
| US4585768A (en) * | 1984-04-10 | 1986-04-29 | Tanabe Seiyaku Co., Ltd. | 1,5-benzothiazepine derivatives and processes for preparing the same |
-
1986
- 1986-01-07 JP JP61001845A patent/JPS62161776A/en active Granted
- 1986-12-15 IE IE326986A patent/IE59359B1/en not_active IP Right Cessation
- 1986-12-19 IL IL81039A patent/IL81039A/en not_active IP Right Cessation
- 1986-12-29 ES ES8603613A patent/ES2003642A6/en not_active Expired
- 1986-12-29 PT PT84036A patent/PT84036B/en not_active IP Right Cessation
- 1986-12-30 FI FI865343A patent/FI865343A/en not_active Application Discontinuation
-
1987
- 1987-01-06 KR KR1019870000022A patent/KR910002879B1/en not_active IP Right Cessation
- 1987-01-06 SU SU874028773A patent/SU1544187A3/en active
- 1987-01-06 CA CA000526793A patent/CA1291134C/en not_active Expired - Fee Related
- 1987-01-06 BG BG077954A patent/BG46747A3/en unknown
- 1987-01-06 DD DD87299117A patent/DD257426A5/en not_active IP Right Cessation
- 1987-01-07 CN CN87100139A patent/CN1030388C/en not_active Expired - Fee Related
- 1987-01-07 AT AT0001687A patent/AT394367B/en not_active IP Right Cessation
- 1987-01-07 HU HU8752A patent/HU198031B/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2736671C1 (en) * | 2020-05-19 | 2020-11-19 | федеральное государственное бюджетное образовательное учреждение высшего образования «Санкт-Петербургский горный университет» | Blocking hydrophobic-emulsion solution with marble chips |
Also Published As
| Publication number | Publication date |
|---|---|
| AT394367B (en) | 1992-03-25 |
| ATA1687A (en) | 1991-09-15 |
| DD257426A5 (en) | 1988-06-15 |
| IL81039A (en) | 1991-07-18 |
| FI865343A (en) | 1987-07-08 |
| HUT45242A (en) | 1988-06-28 |
| ES2003642A6 (en) | 1988-11-01 |
| KR910002879B1 (en) | 1991-05-09 |
| IL81039A0 (en) | 1987-03-31 |
| HU198031B (en) | 1989-07-28 |
| CN87100139A (en) | 1987-08-12 |
| FI865343A0 (en) | 1986-12-30 |
| CN1030388C (en) | 1995-11-29 |
| SU1544187A3 (en) | 1990-02-15 |
| IE59359B1 (en) | 1994-02-09 |
| BG46747A3 (en) | 1990-02-15 |
| JPH0573749B2 (en) | 1993-10-15 |
| PT84036B (en) | 1989-01-17 |
| JPS62161776A (en) | 1987-07-17 |
| KR870007147A (en) | 1987-08-17 |
| PT84036A (en) | 1987-01-01 |
| IE863269L (en) | 1987-07-07 |
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