IE863269L - Process for 1,5-benzothiazepines - Google Patents
Process for 1,5-benzothiazepinesInfo
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- IE863269L IE863269L IE863269A IE326986A IE863269L IE 863269 L IE863269 L IE 863269L IE 863269 A IE863269 A IE 863269A IE 326986 A IE326986 A IE 326986A IE 863269 L IE863269 L IE 863269L
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- lower alkyl
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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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- 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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Abstract
PURPOSE:To economically obtain the titled compound useful as a hypotensor, a cerebral or coronary vasodilator and a platelet coagulation inhibitor, by alkylating 4-hydroxyphenyl group of a compound corresponding to the titled compound to 4-alkoxyphenyl group. CONSTITUTION:The compound of formula II (R<1> is lower alkyl; R<2> is H or lower alkanoyl; X<1> is H or lower alkyl) or its salt useful for the remedy amelio ration or prevention of cerebral diseases such as hypertension, cerebrovascular contraction, etc., cardiac diseases such as stenocardia or thromotic diseases such as cerebral thrombosis, etc., can be produced by alkylating the compound of formula I (R<3> is H or lower alkanoyl; X<2> is H, alkyl or protecting group), removing X<2> when it is a protecting group, optionally removing R<3> when it is lower alkanolyl group and optionally converting the product to its salt. Since the reaction can be performed without causing racemization, an optical isomer can be produced by using an optically active raw material.
[JP62161776A]
Description
9 3 5 9 This invention relates to a novel process for preparing 1,5-benzothiazepine derivatives of the formula: 1 2 wherein R is a lower alkyl group, R is hydrogen atom or a lower alkanoyl group, and X^" is hydrogen atom or a lower alkyl group, or a salt thereof.
U.S. Patent 3,562,257 discloses various benzodiazepine derivatives including 7-chloro-l,5-benzothiazepine derivatives such as 2-(4-methoxyphenyl)-3-hyaroxy(or acetoxy)-5-C2-(dimethylamino)ethyl)-7-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Said U.S. Patent also > -iA- discloses that these benzodiazepine derivatives have antidepressive, trancuilizing anc/or coronary vasodilating activities.
As comoared with these known compounds, the compound (I) of the present invention in which X"*" is a lower alkyl group shows stronger hypotensive and cerebral or coronary vasodilating activities and is more useful for treatment, amelioration and/or prophylaxis of hvpertention; 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 compound (I) of the invention in which X^" is hydrogen atom shows platelet aggregation-inhibiting activity and is useful for treatment, amelioration and/or prophylaxis of thrombotic diseases such as cerebral thrombosis ( cerebral infarction ), transient cerebral ischemia, coronary thrombosis ( myocardial infarction ), pulmonary embolism, peripheral vascular embolism, thromboangiitis and/or other thromboembolism (e.g. the thromboembolism following heart valve replacement). According to the present invention, the compound (I) can be prepared by the step or steps of: i) alkylating a compound of the formula: wherein RJ is hydrogen atom or a lower alkanoyl group and X is hydrogen atom, a lower alkyl group or a protecting group, 2 ii) when X is a protecting group, removing said protecting group therefrom, iii) when R"^ 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 which have been usually employed to protect 2 an amino group may be used as the protecting group X . Examples of such protecting groups include unsubstituted or substituted benzyloxycarbonyl groups such as benzyloxvcarbonvl or p-methoxybenzyloxycarbonyl groups; unsubstituted or substituted lower alkoxycarbonyl groups such as tert.-butoxycarbonyl, J3 , S , 6-trichloroethoxycarbonyl or iodoethoxvcarbonvl groups; and unsubstituted or substituted pnenvl-lower alkyl groups such as benzyl, p-raethoxybenzyl or 3,4-dimethoxybenzvl groups.
The alkylation of this invention can be carried out by treating the compound (II) with a lower alkylating agent. The alkylating agent includes, for example, a lower alkanol, a lower alkyl sulfate such as dimethylsulfate, a lower alkyl ester of alkyl or aryl sulfonate such as methyl tosylate, methyl methanesulfonate and dimethyl 2-oxo-l,3-propane -3- disulfonate, a lower alkyl halice such as methyl iodide and methyl bromide, a lower alkyl quaternary ammonium compound such as trimethvlpnenylammonium hydroxide, a lower alkyl sulfonium or sulfoxonium compound such as trimethylsulfonium hydroxide, trimethylsulfoxonium iodide, a lower alkyl selenoniuin compound such as triinethylsalenonium hydroxide, and a diazo lower alkane such as diazomethane.
When the lower alkanol is used as the alkylating agent, it is preferred to carry out the reaction in the presence of a dehydrating agent. Conventional dehydrating agents such as dicyclohexylcarbodiimide or a mixture of triphenylphosphine and ciazenedicarboxylic acid diethyl ester may be used for this purpose. It is preferred to carry out the reaction at temperature of 0 to 40°C.
When the above-mentioned lower alkyl sulfate, lower alkyl ester of alkyl or aryl sulfonate or lower alkyl haliae is used as the alkylating agent, it is preferred to carry out the reaction in the presence of a base. Examples of such base include inorganic bases such as an alkali metal oxide, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydride or an alkali metal alkoxide, and organic bases such as ethyl diisopropyl amine. It is preferred to carry out the reaction at a temperature between 0 °C and a refluxing temperature, especially at 10 to 40 °C in an inert solvent ( e.g., acetone, acetonitrile, methanol, benzene, dioxane, tetrahvdrofuran, dimethylsulfoxide, dimethvlf ormaruide) . It is also preferred to carry out the reaction in the presence of a phase-transfer catalyst such as tetrabutylammonium fluoride.
On the other hand, when the lower alkyl quaternary ammonium compound, lower alkyl sulfonium or sulfoxoniun compound or lower alkyl selenonium compound is used as the alkylating agent, it is preferred to carry out the reaction at a temperature between 10°C and a refluxing temperature, especially 50~100 °C either in an inert solvent or without solvent. Toluene, dioxane, methanol, dimethylformamide and dimethylsulfoxide are suitable as the solvent.
When the diazo lower alkane is used as the alkylating agent, the reaction is preferably carried out at a temperature of 0 to 40°C, especially 20 to 30°C in an inert solvent. Dioxane, tetrahydrofuran, methanol and the mixture 3 thereof are suitable as the solvent. When R of tne starting compound (II) is a lower alkanoyl group, it is preferred to carry out the reaction in the presence of fluoroboric acid or silica gel.
In carrying out the above-mentioned alkylation reaction, it is particularly preferred that the lower alkyl sulfate, lower alkyl sulfonate or lower alkyl halide is used 2 as the alkylating agent when X of the starting compound (II) is hydrogen atom and R"* is the lower alkanoyl group; or -5- alternatively the lower alkyl quaternary ammonium compound, lower alkyl sulfcnium or sulfoxonium compound, lower alkyl selenonium compound or diazo lower alkane is used as the 2 3 alkylating agent when both X and R"1 of the starting compound (II) are hydrogen atom. 2 'When X of the thus-obtained product is a protecting group, removal of said 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, said group may be readily removed by treating with an acid such as hydrogen bromide, hydrogen chloride or trifluoroacetic acid in a solvent. When the protecting group is a substituted lower alkoxy carbonyl, said 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, said 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 benzyloxycarbonyl group is preferably carried out by treating the product (i.e., the compound the imino group of which is protected by the unsubstituted or substituted phenyl lower -6- alkyl group) with benzyloxycarbonyl halice such as benzyloxycarbonyl chloride at a temperature between 50 and 130°C in a solvent.
When R" is the lower alkanoyl group, the protecting group and said lower alkanoyl group may be removed simultaneously, or the protecting group may be removed without removal of said lower alkanoyl group. These reactions can be -controlled by changing the reaction conditions such as the amount of the reaction agents, the reaction time and/or the reaction solvent used.
If required, the compound (I) of the present invention thus obtained may be converted into acid addition salts thereof by treating it with an acid. Examples of acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodice, perchlorate, sulfate or phosphate, organic acid addition salts such as 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 compound (II) as the starting compound.
The starting compound (II) is prepared, for example, by the step or steps of reacting 3-(4- benzyloxypheny1)glycidic acid methyl ester with 5-chloro-2- -7- aminothiophenol to give 2-(4-cenzyloxyphenyl)-3-hydroxy-8-chloro-2,3-dihvdro-l,5-benzothiazepin-4(5K)-one or a salt thereof, condensing the product with a compound of the formula: C H Y-CHzCHzN^ ' (m) XX2 2 wherein Y is a halogen atom and X is the same as defined above, or a salt thereof to aive a conroound of the formula: ^"""y o-chz— (IV) JHa CHzCHzN C XX2 2 wherein X is the same as defined above, removing benzyl group from the compound (IV), and if required, converting hydroxy group of the thus-obtained product at 3-position of the benzothiazepine ring into a lower alkanoyloxy group before or after removal of said benzyl group.
While 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., (-r-)-cis, (-)-cis, (+)-trans, and (-)-trans) due to the two asymmetric carbon atoms -8- involved therein, all of these isomers or a mixture thereof are included within the scope of the invention. Among these isomers, however, the cis isomer of the compound (I) is preferred for medicinal use.
Example 1 6S0 mg of (+)-cis-2-(4-hydroxyphenyl)-3-hydroxy-5-C 2-(N,N-dimethylamino)ethyl}-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one are dissolved in 20 ml of tetrahydrofuran. 78 mg of sodium hydride (60% oily) are added thereto at room temperature and stirred for 30 minutes at the same temperature. A solution of 24 5 mg of dimethyl sulfate in 10 ml of dimethylformamide is added thereto, and the mixture is stirred for 1 hour at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 509 mg of (+)-cis-2-(4-methoxyphenvl)-3-hvdroxy-5-(2-(N,N-dimethy1amino)ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one are obtained.
M.p. 122-124°C (decomp.) (cx}^ +144.6° (C=0.85, methanol) Examples 2 to 4 -9- The corresponding starting compounds are treated in the same manner as described in Example 1 to give the compounds shown in Table 1.
Table 1 // \\ CHzCHzN ( 0 ) xXz ( I ) (R1 , X' and Xz = -Cll3, R3= R2) C H 2 CII2 N Ex. No.
Compound (I) R2 Ootical ; Properties 1 activity j 2 -H cis-(-) M.p. 121-123°C (decomp.) (cO20 -14 2 . 7 0 (C=1. 04 , methanol) 1 3 -COCH-s cis-(+) Maleate(recrystallized from 1 ethar.ol-ether) M.p. 158-160°C Ca}20 + 75.4 °(C=1.0,methanol) 4 -COCH3 cis-(-) Hydrochloride M.p. 12 8-132°C(decomp.) CcO20 -93.3 °(C=0.872, ethanol) Example 5 -10- 210 mg of (+)-cis-2-(4-hydroxvphenyl)-2-acetoxy-5-(2-(N-methylamino)ethyl)-8-chlcro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one, 250 mg of potassium carbonate and 140 mg of dimethylsulfate are dissolved in 5 ml of methanol, and the solution is.stirred at room temperature overnight. Insoluble materials are filtered off , and the filtrate is evaporated to remove the solvent. The residue is 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. 212 mg of ( + )- cis-2-(4-methoxyphenyl)-3-acetoxy-5-C 2-(N,N-dimethylamino)ethyl)-8-chloro-2, 3-dihydro-l,5-benzothiazepin-4(5K)-one maleate are obtained.
The physico-chemical properties of this product are identical with those of the product prepared in Example 3. Example 6 (1) (-)-cis-2-(4-hycroxyphenyl)-3-hydroxy-5-C2-(N-benzyl-N-methylamino)ethyl)-8-chloro-2,3-dihvdro-l,5-benzothiazepin-4(5H)-one is treated in the same manner as described in Example 1 to give (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-C 2-(N-benzyl-N-methylamino)ethyl}-3-chloro-2,3-dihyaro-1,5-benzothiazepin-4(5H)-one.
Perchlorate (recrystallized from ethanol) M.p. 161-163°C (decomp.) CoO20 -76.4°(C=0.589, methanol) D -11- (2) 4.3 g of the product obtained in paragraph '(1) are dissolved in 50 ml of benzene and refluxed. A solution of 4.55 g of benzyloxycarbonyl chloride in 10 ml of benzene is added aropwise thereto for 15 minutes. The solution is refluxed for 1 hour, cooled to room temperature, and evaporated to remove the solvent. To the residue are added 30 ml of ethanol and 50 ml of 5% aqueous sodium hydroxide, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with water, extracted with chloroform. The extract is washed with water, dried and evaporated to remove the solvent. 4.79 g of (-)-cis-2-(4-methoxvphenvl)-3-hydroxy-5-(2-(N-benzvloxycarbonyl-N-methylamino)ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5K)-one are obtained.
IRv CKC13 (cm-1): 3510, 1695, 1660 max (a)20 -133.30(C=0.582, methanol) (3) 1.07 g of the product obtained in paragraph (2) are dissolved in 2 ml of benzene, and 1.7 ml of a 25% hydrogen bromide-acetic acid solution are added thereto. The mixture is stirred for 2 hours at room temperature.
Ether is added thereto, and the precipitates are collected by filtration and washed with ether. To the precipitates are added water and benzene, and the mixture is made alkaline -12- with potassium carbonate. The benzene layer is washed with water, dried, and evaporated to remove the solvent. To the filtration, and recrystallized from a mixture of ethyl acetate and n-hexane. 0.47 g of (-)-cis-2-(4-methoxyphenyl) -3-hydroxy-5- ( 2- (N'-methy 1 amino) ethyl )-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one is obtained.
Fumarate (recrystallized from ethanol) M.p. 164-167°C(cecomp.) Examples 7 to 9 (1) The corresponding starting compounds are treated in the same manner as described in Example 6 —(1) to give the compounds shown in Table 2. residue is added ether. The precipitates are collected by M.p. 142-145°C (oO20 -147 . 7 °(C=0 . 814 , chloroform) u Table 2 CI / \y OH CI N-\\ | 0 Clt, CIIzCIIzN<^ / VOR | 0 CH3 CHzCHzN XXZ X 2 (V) (n) (R 1 = -CII3. x2= -CllzCblU) -13- Ex . No. 1 Compound (V) | Optical 3 ' R" j activity Prcoerties 7 -K cis-(+) Perchlorate(recrystallized from ethanol) M.p. 161-16 3°C(decomp.) Ca)20 +76.5°(C=0.446, methanol) 8 -COCH, 3 cis-(-) Oxalate(recrystallized from ethanol) M.p. 19 2-19 4°C(decomp.) Cco£° -9 6 . 5 ° (C=1. 0 , dimethyformamide) 9 -coch3 CiS-(-r) Oxalate(recrystallized from ethanol) M.p. 191-194°C(decomp.) CcOp0 +96.8°(C=0.73, dimethyformamide) (2) The products (V) obtained above are treated in the same manner as described in Example 6—(2) to give the compounds shown in Table 3.
Table 3 //~W C1 y- 0 R 1 C,u C II z C II z N / \ (V-a) -£} Cl ^ OR 1 _/0R > I ^0 CH ( R 1 = - CII3) CilzCllzN (V-b) -/V - o o c ii 2 —v^_y Ex.
Compound (V-b) Optical Properties No. activity 7 -H cis-(+) (o020+132.6°(C=0.550, methanol) 8 -COCH3*) cis-(-) IRVC"C13 (cm_1):1740, 1685 max CcO20 -115.4 °(C=1.0, methanol) 9 -COCH„*) cis-(+) (a)20 +115.5 °(C=1.0, methanol) note: *): After the reaction, the residue is not treated with ethanol-aqueous sodium hydroxide. (3) The products (V-b) obtained above are treated in the same manner as described in Example 6-(3) to give the compounds shown in Table 4.
Table 4 (R 1 = - CH 3, Rz= -II, R 3= -H or -C0CH3) -15- Ex.
Compound (I-a) No.
Optical activity Properties 7 cis-(+ ) Hydrochloride 1/2 hydrate (recrystallized from the mixture of ethnol and ether) M.p. 137-140 °C (c02<"> +83 . 4 ° (C=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-hydroxypnenyl)-3-hydroxy-5- C 2-(N-benzyl-N-methylamino)ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one are dissolved in 20 ml of toluene, and a solution of 490 mg of benzyloxycarbonyl chloride in 10 ml of toluene are added thereto at 80°C. The mixture is stirred at 30°C for 5 hours. After the reaction, the solvent is distilled off. To the residue are added 10 ml of 5% aqueous sodium hydroxide and 10 ml of methanol, and the mixture is stirred at room temperature for 2 hours. The mixture is extracted with ethyl acetate. The extract is washed with water, dried, and evaporated to the solvent.
Then the residue is purified by silica gel column chromatography (solvent; chloroform : methanol =9 : 1) to -16- give 410 mg of (-)-cis-2-(4-hydroxypnenyl)-3-hydroxv-5-C2-(N-benzyioxycarbonyl-N-methylamino ) ethyl )-8-chloro-2 , 3-cihydro-1,5-benzothiazepin-4(5H)-one. (2) A mixture of 410 mg of the product obtained in paragraph (1), 340 mg of potassium carbonate, 170 mg of methyl iodide and 10 ml of methanol is stirred at room temperature for 40 hours. After the reaction, the mixture is evaporated to remove the solvent, and the residue is dissolved in ethyl acetate. The solution is washed with 10% aqueous sodium hydroxide and water, dried, and evaporated to remove the solvent. 315 mg of (-)-cis-2-(4-methoxyphenyl)-3-hydroxv-5-C 2-(N-benzyloxvcarbonyl-N-methylamino)ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one are obtained.
The physico-chemical properties of this product are identical with those of the product prepared in Example 6-(2) . (3) The product obtained in paragraph (2) is treated in the same manner as described in Example 6-(3), whereby (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-C 2-(N- methvlamino)ethylJ-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one is obtained.
Example 11 (1) (-)-cis-2-(4-hydroxyphenvl)-3-acetoxy-5-C 2-(N-benzy1-N-methy1amino)ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one is treated in the same manner as -17- described in Example 8-(2) to give •(-)-cis-2-(4-hydroxyphenyl)-3-acetoxv-5-(2-(N-benzyloxycarbonyl-N-methylamino)ethyl;-8-cnloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one. (cO2^ -106 . 0 °(C=0 . 50 , chloroform) (2) The product obtained in paragraph (1) is treated in the same manner as described in Example 10-(2) to give (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-C 2-(N- benzyloxycarbonyl-N-methy1amino)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 a-nd 95 ml of dichloromethane are mixed under ice-cooling , and the mixture is stirred at room temperature for 3 hours. After the reaction, dichloromethane is distilled off, and ether is added to the residue. After the precipitates are washed with ether, the precipitates are dissolved in water. The solution is neutralized with potassium carbonate, and extracted with ether. The extract is washed with water, dried and evaporated to remove the solvent. The residue is converted into the oxalate, and recrystallized from methanol. 18.7 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N- methy1amino)ethyl}-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one oxalate are obtained. -18- M.p. 174-176°C CcO20 -74.2 °(C = 0. 314, methanol) Example 12 64 5 mg of trinethylammonium tosylate are added to sodium rnethoxide ( prepared from 4 6 mg of sodium metal and 4.5 ml of methanol), and the mixture is stirred at room temperature for 3 hours. Insoluble materials are filtered off, and the filtrate is added to 20 ml of a toluene solution containing 570 mg of (-)-cis-2-(4-hvdroxyphenyl)-3-hydroxv-5 — C 2 —(N-methy1amino)ethyl}-3-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one. After methanol is distilled off, the solution is refluxed for 2 hours. After the reaction, the mixture is evaporated to remove the solvent. The residue is purified by silica gel column chromatography( solvent ; chloroform : ethanol =95 : 5) and recrystallized from the mixture of ethyl acetate and n-haxane. 275 mg of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-C 2-(N-methylamino)ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one are obtained.
The physico-chemical properties of this product are identical with those of the product prepared in Example 6-(3) .
(Preparation of Starting Compounds) Preparation 1 -19- (1) A mixture of (+)-trans-2-(4-benzyloxypnenyl)glycidic acid methyl ester and 5-chloro-2-aminothiophenol is heated at 160 °C for 16 hours. (S)-N-(2-naphthalenesulfonyl)pvrrolidine-2-carbonyl chloride and pyridine are added to the reaction solution, and the solution is stirred. After the reaction, the product is separated by silica gel column chromatography( solvent; benzene : ethyl acetate =4:1) into the (+)-isomer and (-)-isomer thereof. After said separation, potassium carbonate , water and methanol are added to each isomers, and the mixture is stirred at room temperature overnight. Recrystallization of each products from ethyl acetate gives (+)- and (-)-isomers of cis-2-(4-benzyloxyphenyl)-3-hydroxy-S-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1/5 ethyl acetate, respectively. (+)-isomer 1/5 ethyl acetate: (a)20 -74.2°(C=1.00, dimethylformamide) (-)-isomer 1/5 ethyl acetate: 20 CoOD -75.0°(C=1.00, dimethylformamide) (2) A mixture of (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxv-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5K)-one, 2-(N-benzyl-N-methylamino)ethyl chloride hydrochloride, potassium carbonate, acetone, ethyl acetate and water is refluxed. After the reaction, insoluble materials are filtered off, and the filtrate is evaporated to remove the -20- solvent. The residue is converted into oxalate and recrystallized from a mixture of methanol and ether to give (+ )-cis-2-(4-benzyloxyphenyl)-3-hvdroxy-5-C2-(N-benzyl-N-methylamino )ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one oxalate.
M.p. 108-115°C +85 . 8 0 (c=l. 00 , methanol) d (3) The product obtained in paragraph (2) ( free base) is dissolved in pyridine, a solution of acetyl chloride in dichloromethane is added thereto, and the mixture is stirred. After the reaction, the mixture is evaporated to remove the solvent, and the residue is dissolved in ethyl acetate. The solution is washed with water, 5% aqueous sodium bicarbonate anc water, successively. Then, the solution is dried and evaporated to remove the solvent. The residue is converted into the oxalate, and recrystallized from the mixture of methanol and ether. (+)-cis-2-(4-benzyloxyphenyl)-3-acetoxy-5-(2-(N-benzyl-N-methylamino )ethyl )-8-cnloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one oxalate is obtained.
M.p. 173-175°C Ccx)2^ +78 . 4 0 (C=l. 00 , methanol) (-)-cis isomer oxalate M.p. 172-175°C -21- (4) The product obtained in paragraph (3) (free base) is dissolved in toluene, anc a solution of benzyloxycarbonyl chloride in toluene is added dropwise thereto. The mixture is stirred under heating. After the reaction, the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent; chloroform : ethyl acetate = 95 : 5), and recrystallized from the mixture of ethyl acetate and n-hexane. (+)-cis-2-(4-benzyloxyphenyl)-3-acetoxy-5~C 2-(N-benzvloxycarbonyl-N-methy1amino)ethyl}-8-chloro-2,3-aihydro-1,5-benzothiazepin-4(5H)-one is obtained. (a+79.00(C=l.00, chloroform) (-)-isomer -79.2°(C=l.00, chloroform) (5) The product obtained in paragraph (4) is dissolved in ethyl acetate, and thereto is added 25% hydrogen bromide-acetic acid under cooling. After the reaction, the solvent is distilled off. The residue is washed with ether, neutralized with conc. aqueous ammonia to give the corresponding free base, and extracted with chloroform. The extract is washed with water, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography and converted into the oxalate. (+)-cis-2- -22- ( 4-hycroxyphenyi ) -2-acetoxy-5-C 2- (N-merhylami.no) ethyl j-3-chloro-2,2-dihydro-l,5-benzothiazepin-4(5H)-one oxalate is obtained.
M.p. 186-1S9 °C CcO^ +61. 2 ° (C=0 . 50 , methanol) (- ) -cis-isomer M.p. 187-189°C Caj2^ -81.6°(C=0.50, methanol) Preraration 2 (1) ( + )-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-C 2-(N-benzvl-N-methylamino)ethyl)-S-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one is treated in the same manner as described in Preparation 1—(4 ) to give (+)-cis-2-(4-benzyloxyphenyl)-2-hydroxv-5-(2-(N-benzyloxycarbonyl-N-methylanuno)ethyl)-6-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one.
M.p. 94-96°C CoO20 +126.0°(C=l.00, chloroform) (-)-cis-isomer M.p. 9 3-9 5 °C Ca)20 -125.6°(C=l.00, chloroform) -23- (2) The product obtained in paragraph (1) is treated in the same manner as described in Preparation 1—(5). The free base obtained is converted to the corresponding 2 —(4 — hycroxv-benzoyl)benzoate, and recrystallized from aqueous ethanol to give (+)-cis-2-(4-hydroxvphenyl)-3-hycroxv-5-C2-(N-methylamino)ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5H)-one 2-(4-hydroxvbenzoyl) benzoate 3/2hvdrate.
M.p. 124-127°C (a)20 +198.1°(C=0.12 0, methanol) Lf (-)-cis-isomer 2-(4-hydrcxy-benzoyl)benzoate 3/2 hydrate M.p. 124-127 °C -197 . 5 c (C = 0 .120 , methanol) Preparation 3 (1) (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5K)-one and 2-(N,N-dimethylamino)ethyl chloride hydrochloride are treated in the same manner as described in Preparation 1—(2) to give (+)-cis-2-(4-benzyloxyphenyl)-3-hydroxy-5-C 2-(N,N-dimethyl-amino)ethyl)-3-chloro-2, 3-dihydro-l,5-benzothiazepin-4(5H)-one oxalate.
M.p. 148-151°C(decomp.) (a)20 +94.0°(C=1.00, methanol) -24- (-)-cis-isomer oxalate M.p. 14 9-152°C(decomp.) CcO^ -94 . 2 °(C=1. 00, methanol) (2) A mixture of the product obtained in paragraph (1) (free base), acetic anhydride and pyridine is stirred under heating. After the reaction, the solvent is distilled off, and the residue is converted into the oxalate, and recrystallized from a mixture of methanol and ether. ( + )-cis-2-(4-benzyloxyphenyl)-3-acetoxy-5-(2-(N,N-dimethylamino )ethyl)-8-chloro-2,3-dihydro-l,5-benzothiazepin-4(5K)-one 1/2 oxalate is obtained.
M.p. 168-172°C(decomp.) CoO20 +78.4°(C=1.00, methanol) (-)-cis-isomer 1/2 oxalate M.p. 163-171°C(decomp.) (&j2^ -78 . 8 c (C=1. 00 , methanol) (3) The product obtained in paragraph (2) ( free base) is dissolved in acetic acid, and 25% hydrogen bromide-acetic acid is added thereto under cooling and stirred.
After the reaction, the solvent is distilled off. The residue is washed with ether, neutralized with conc. aqueous ammonia to give the free base, and extracted with chloroform. The extract is washed with water, dried, and evaporated to -25- remove the solvent. The residue is converted into the oxalate and recrystallized from ethanol. (-*-)-cis-2-(4-hvdroxyphenyl)-5-acetoxy-5-( 2 - (N,N-dimethylamino)ethyl)-8-chloro-2 , 3-dihvdro-l, 5-'oenzothiazepin-4 ( 5K )-one oxalate 1 hydrate is obtained.
M.p. 142-14S °C CaD20 +79.2°(C=0.50, methanol) (-)-cis-isomer oxalate 1 hydrate M.p. 143-149°C CcO20 -73.3°(C=0.50, 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 c> ,c^O-°-c"-o VoR3 N — I 0 CH: CIlzCHiN ^ (IV) Xxz -26- ! or i"1- • i i j NO .
Ccmoot i R3 1 nd (II) x2 Optical activitv Properties 1 i j ! 4 i i I -H ~CK3 cis-( + ) i 2-(4-hvdroxybenzoyl)benzoate (recrystallized from a mixture of acetone and isopropyl ether) M.p 165-170°C(dec.) Ca)2^ +79.80(C=l.00, methanol) D cis-(-) 2-(4-hvdroxybenzoyl)benzoate (recrystallized from a mixture 1 of acetone and isopropyl ether); M.p 16 6-170°C(dec.) (a)2^ -80.10(C=l.00, methanol) 5 -H "CH2C6K5 i JOxalate(recrystallized from a cis-(+) imixture of ethanol and ether) i j M.p 130-135 °C(dec.) » i(o020 +97.60(C=0.50, methanol) j ( l |Oxalate(recrystallized from a | cis-(-) imixture of ethanol and ether) iM.o 130-135°C(dec.) < Ua)20 -97.5°(C=0.50, methanol) i D 1/2 oxalate 1 hydrate -27- cis-(+) (recrystallized from a mixture of acetone and ether) M.p 10 3-113°C(dec.) (cO20 +78.4°(C=1.00, methanol) D 6 -COCK- -CH2C6H5 1/2 oxalate 1 hydrate (recrystallized from a mixture cis-(-) of acetone and ether) M.p 103-114°C(dec.) 20 (a)D -78.8°(C=l.00, methanol) -28-
Claims (7)
1. A process for preparing a 1,5-benzothiazepine derivative of the formula: wherein R1 is a lower alkyl group, R2 is hydrogen atom or a lower alkanoyl group, and is hydrogen atom or a lower alkyl group, or a salt thereof which comprises tfie step or steps: i) alkylating a compound of the formula: 3 2 wherein R is hydrogen atom or a lower alkanoyl group, and X is hydrogen atom, a lower alkyl group, or a protecting group, 2 ii) when X is a protecting group, removing said protecting group therefrom, -29- iii) when R is £ lower alkanoyl group, optionally removing said lower alkanoyl therefrom, and iv) if required, further converting the product into a salt thereof.
2. The process claimed in Claim 1 wherein the alkylation is conducted by treating with a lower alkanol at 0 to 40 °C in the presence of a dehydrating agent.
3. The process claimed in Claim 1 wherein the alkylation is conducted by treating with a lower alkyl sulfate, a lower alkyl sulfonate or a lower alkyl halide at a temperature between 0 °C and a refluxing temperature in the presence of a base in an inert solvent.
4. The process claimed in Claim 1 wherein the alkylation is conducted by treating 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 a refluxing temperature.
5. The process claimed in Claim 1 wherein the alkylation is conducted by treating with a diazo lower alkane at 0 to 40 °C , especially at 20 to 30 °C in an inert solvent.
6. A process according to Claim 1 for preparing a 1,5-benzothiazepine derivative of the formula (I) given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described with particular reference to the accompanying Preparations and Examples.
7. A 1,5-benzothiazepine derivative of the formula (I) given and defined in Claim 1 or a salt thereof, whenever prepared by a process claimed in a preceding claim. Dated this the 15th day of December, 1986 F. R. H2LLY & CO. BY: EXECUTIVE 27 Clyde Road, Balltbridge, Dublin 4. AGENTS FOR THE APPLICANTS.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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JP61001845A JPS62161776A (en) | 1986-01-07 | 1986-01-07 | Production of 1,5-benzothiazepine derivative |
Publications (2)
Publication Number | Publication Date |
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IE863269L true IE863269L (en) | 1987-07-07 |
IE59359B1 IE59359B1 (en) | 1994-02-09 |
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Application Number | Title | Priority Date | Filing Date |
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IE326986A IE59359B1 (en) | 1986-01-07 | 1986-12-15 | Novel process for preparing 1,5-benzothiazepine derivatives |
Country Status (14)
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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) |
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US5580867A (en) * | 1994-09-09 | 1996-12-03 | Universite De Montreal | Myocardial protection during ischemia and reperfusion |
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 |
Family Cites Families (6)
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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 DD DD87299117A patent/DD257426A5/en not_active IP Right Cessation
- 1987-01-06 KR KR1019870000022A patent/KR910002879B1/en not_active IP Right Cessation
- 1987-01-06 BG BG77954A patent/BG46747A3/en unknown
- 1987-01-06 CA CA000526793A patent/CA1291134C/en not_active Expired - Fee Related
- 1987-01-06 SU SU874028773A patent/SU1544187A3/en active
- 1987-01-07 HU HU8752A patent/HU198031B/en not_active IP Right Cessation
- 1987-01-07 AT AT0001687A patent/AT394367B/en not_active IP Right Cessation
- 1987-01-07 CN CN87100139A patent/CN1030388C/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
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ES2003642A6 (en) | 1988-11-01 |
IE59359B1 (en) | 1994-02-09 |
CN1030388C (en) | 1995-11-29 |
ATA1687A (en) | 1991-09-15 |
IL81039A (en) | 1991-07-18 |
AT394367B (en) | 1992-03-25 |
FI865343A (en) | 1987-07-08 |
IL81039A0 (en) | 1987-03-31 |
CA1291134C (en) | 1991-10-22 |
PT84036B (en) | 1989-01-17 |
FI865343A0 (en) | 1986-12-30 |
BG46747A3 (en) | 1990-02-15 |
HUT45242A (en) | 1988-06-28 |
PT84036A (en) | 1987-01-01 |
SU1544187A3 (en) | 1990-02-15 |
KR910002879B1 (en) | 1991-05-09 |
KR870007147A (en) | 1987-08-17 |
JPH0573749B2 (en) | 1993-10-15 |
DD257426A5 (en) | 1988-06-15 |
CN87100139A (en) | 1987-08-12 |
JPS62161776A (en) | 1987-07-17 |
HU198031B (en) | 1989-07-28 |
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