NO172286B - PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES - Google Patents
PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES Download PDFInfo
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- NO172286B NO172286B NO922253A NO922253A NO172286B NO 172286 B NO172286 B NO 172286B NO 922253 A NO922253 A NO 922253A NO 922253 A NO922253 A NO 922253A NO 172286 B NO172286 B NO 172286B
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- 238000000034 method Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- -1 alkali metal hydrogen carbonate Chemical class 0.000 claims description 5
- KJFRSZASZNLCDF-UHFFFAOYSA-N 1,5-benzothiazepine Chemical class S1C=CC=NC2=CC=CC=C12 KJFRSZASZNLCDF-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 229940093499 ethyl acetate Drugs 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
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- 239000000047 product Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- LCXGFVXUJZJODY-UHFFFAOYSA-N n-methylmethanamine;toluene Chemical compound CNC.CC1=CC=CC=C1 LCXGFVXUJZJODY-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- AGEJIUDWIJYIHH-SJORKVTESA-N (2S,3S)-8-chloro-5-(2-chloroethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4-one Chemical compound COC1=CC=C(C=C1)[C@@H]1SC2=C(N(C([C@@H]1O)=O)CCCl)C=CC(=C2)Cl AGEJIUDWIJYIHH-SJORKVTESA-N 0.000 description 2
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 2
- KAANMZCKNKVSAA-CABCVRRESA-N (2s,3s)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-3,5-dihydro-2h-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)NC2=CC=C(Cl)C=C2S1 KAANMZCKNKVSAA-CABCVRRESA-N 0.000 description 1
- DWOKUCFPFUCSID-MOPGFXCFSA-N (2s,3s)-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)N(CCN(C)C)C2=CC=C(Cl)C=C2S1 DWOKUCFPFUCSID-MOPGFXCFSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KYWXRBNOYGGPIZ-UHFFFAOYSA-N 1-morpholin-4-ylethanone Chemical compound CC(=O)N1CCOCC1 KYWXRBNOYGGPIZ-UHFFFAOYSA-N 0.000 description 1
- FMMYTRQXHORTCU-UHFFFAOYSA-N 2-chloroethyl methanesulfonate Chemical compound CS(=O)(=O)OCCCl FMMYTRQXHORTCU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- RHVNLTPHWLWAKR-MOPGFXCFSA-N [(2S,3S)-8-chloro-5-(2-chloroethyl)-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate Chemical compound COC1=CC=C(C=C1)[C@@H]1SC2=C(N(C([C@@H]1OC(C)=O)=O)CCCl)C=CC(=C2)Cl RHVNLTPHWLWAKR-MOPGFXCFSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
Den foreliggende søknaden er avdelt fra NO patentsøknad 913388. The present application is divided from NO patent application 913388.
Den foreliggende oppfinnelsen angår en framgangsmåte for framstilling av 1,5-benzontiazepinderivater angitt ved formelen: The present invention relates to a process for the production of 1,5-benzothiazepine derivatives indicated by the formula:
hvor R<1> er en lavere alkoksygruppe, R2 er hydrogen eller en lavere alkanoylgruppe, en av R3 og R4 er et halogenatom, og den andre er hydrogen, og hver av R<3> og R<6> er en lavere alkylgruppe. where R<1> is a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R3 and R4 is a halogen atom, and the other is hydrogen, and each of R<3> and R<6> is a lower alkyl group.
1,5-benzotiazepinderivatene (I) og et farmasøytisk akseptabelt salt derav fremstilt ved tilsats av syre er egnede farmasøytiske forbindelser med en utmerket hypotensiv aktivitet, cerebral eller koronar vasodilaterende aktivitet og/eller blodplate sammenhopningsinhiberende aktivitet og er kjent fra norske utlegningsskrifter 162518 og 163488, og blant forbindelsene (I), er en forbindelse hvor R<2 >er hydrogenatom også egnet som et mellomprodukt for framstilling av farmasøytiske midler. The 1,5-benzothiazepine derivatives (I) and a pharmaceutically acceptable salt thereof prepared by the addition of acid are suitable pharmaceutical compounds with an excellent hypotensive activity, cerebral or coronary vasodilatory activity and/or platelet aggregation inhibitory activity and are known from Norwegian explanatory documents 162518 and 163488, and among the compounds (I), a compound where R<2 >is hydrogen atom is also suitable as an intermediate for the production of pharmaceuticals.
Beskrivelse av de foretrukne utførelsesformene Description of the preferred embodiments
Eksempler på forbindelsen (I) under den foreliggende oppfinnelsen kan omfatte forbindelse hvori R1 er en lavere alkoksygruppe, R2 er hydrogen eller en lavere alkanoylgruppe, en av R<3> eller R<4 >er et halogenatom, og den andre er hydrogenatom, og hver av R<5> og R<6> er en lavere alkylgruppe. Examples of the compound (I) under the present invention may include compounds in which R1 is a lower alkoxy group, R2 is hydrogen or a lower alkanoyl group, one of R<3> or R<4> is a halogen atom, and the other is a hydrogen atom, and each of R<5> and R<6> is a lower alkyl group.
I de ovenfor nevnte eksempler på 1,5-benzotiazepinderivatet (I), inkluderer den lavere alkylgruppen, den lavere alkoksygruppen og den lavere alkanoylgruppen en alkylgruppe med fra 1 til 6 karbonatomer, en alkoksygruppe med fra 1 til 6 karbonatomer og en alkanoylgruppe med fra 2 til 6 karbonatomer, respektive. In the above-mentioned examples of the 1,5-benzothiazepine derivative (I), the lower alkyl group, the lower alkoxy group and the lower alkanoyl group include an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms and an alkanoyl group having from 2 to 6 carbon atoms, respectively.
Foretrukne eksempler på disse gruppene er en alkylgruppe med fra 1 til 4 karbonatomer, en alkoksygruppe med fra 1 til 4 karbonatomer og en alkanoylgruppe med fra 2 til 5 karbonatomer. Preferred examples of these groups are an alkyl group with from 1 to 4 carbon atoms, an alkoxy group with from 1 to 4 carbon atoms and an alkanoyl group with from 2 to 5 carbon atoms.
I følge den foreliggende oppfinnelsen kan forbindelsen (I) fremstilles ved å la en forbindelse angitt med formelen: According to the present invention, the compound (I) can be prepared by allowing a compound represented by the formula:
hvor X<1> er et halogenatom eller en alkylsulfonyloksygruppe, og R<1>, R<2>, R<3> og R<4> har samme betydning som definert ovenfor, where X<1> is a halogen atom or an alkylsulfonyloxy group, and R<1>, R<2>, R<3> and R<4> have the same meaning as defined above,
å reagere med et amin angitt med formelen: to react with an amine represented by the formula:
hvor R<5> og R6 har samme betydning som angitt ovenfor, where R<5> and R6 have the same meaning as stated above,
Reaksjonen mellom forbindelsen (II) og aminet (HI) eller et salt derav kan utføres i et egnet løsningsmiddel med eller uten en base til stede. I forbindelsen (II) kan X1 omfatte et halogenatom slik som fluoratom, kloratom, bromatom og jodatom, eller en alkylsulfonyloksygruppe slik som metylsulfonyloksygruppe. Aminet (HI) kan også brukes i fri tilstand eller som et salt derav i reaksjonen ovenfor. Eksempler på et slikt salt kan omfatte konvensjonelle salt fremstilt ved tilsats av syre slik som saltsyre, bromsyre, sulfat, nitrat, etc. Når det gjelder basen kan der nevnes alkalimetallhydroksid, alkalimetallkarbonat, alkalimetall hydrogenkarbonat, tertiært amin, etc., og også aminet (EO) kan brukes for dette formål. Den foreliggende reaksjonen utføres fortrinnsvis i et egnet løsningsmiddel (for eks. dimetylformamid, dietylformamid, dimetylacetamid, N-formylmorfolin, N-acetylmorfolin, dimetylsulfoksid, diglym, dietyleter, tetrahydrofuran, dimetoksyetan, dioksan, pyridin, alkanol, acetonitril, aceton, metyletylketon, etylacetat, metylacetat, metylpropionat, etylpropionat, benzen, xylen, toluen, etc.) ved en temperatur mellom 0°C og 150°C. The reaction between the compound (II) and the amine (HI) or a salt thereof can be carried out in a suitable solvent with or without a base present. In the compound (II), X1 may comprise a halogen atom such as a fluorine atom, chlorine atom, bromine atom and iodine atom, or an alkylsulfonyloxy group such as a methylsulfonyloxy group. The amine (HI) can also be used in the free state or as a salt thereof in the above reaction. Examples of such a salt may include conventional salts produced by the addition of acid such as hydrochloric acid, bromic acid, sulfate, nitrate, etc. As for the base, mention may be made of alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, tertiary amine, etc., and also the amine ( EO) can be used for this purpose. The present reaction is preferably carried out in a suitable solvent (for example dimethylformamide, diethylformamide, dimethylacetamide, N-formylmorpholine, N-acetylmorpholine, dimethylsulfoxide, diglyme, diethylether, tetrahydrofuran, dimethoxyethane, dioxane, pyridine, alkanol, acetonitrile, acetone, methylethylketone, ethylacetate , methyl acetate, methyl propionate, ethyl propionate, benzene, xylene, toluene, etc.) at a temperature between 0°C and 150°C.
Da reaksjonen ifølge den foreliggende oppfinnelsen som nevnt ovenfor går uten medfølgende racemisering, kan forbindelsen (I) fremstilles som en optisk aktiv forbindelse ved bruk av en optisk aktiv forbindelse (II) som utgangsmateriale. Blant forbindelsene (I) er dessuten forbindelser hvor R<2 >er hydrogen også nyttig som et syntetisk mellomprodukt, siden denne forbindelsen kan konverteres ved acylering til en forbindelse (f) hvor R<2> er en lavere alkanoylgruppe. Since the reaction according to the present invention as mentioned above proceeds without accompanying racemization, the compound (I) can be prepared as an optically active compound using an optically active compound (II) as starting material. Among the compounds (I), compounds where R<2> is hydrogen are also useful as a synthetic intermediate, since this compound can be converted by acylation to a compound (f) where R<2> is a lower alkanoyl group.
Forbindelsen (I) og forbindelsen (II) omfatter også enten to slag stereoisomerer (det vil si, cis og trans-isomerer) eller 4 slag optiske isomerer (det vil si, (+) -cis, (-)-cis, (+)-trans og (-)-trans isomerer) og blandinger derav basert på asymetriske karbonatomer (2) i molekylet. The compound (I) and the compound (II) also include either two kinds of stereoisomers (that is, cis and trans isomers) or 4 kinds of optical isomers (that is, (+)-cis, (-)-cis, (+ )-trans and (-)-trans isomers) and mixtures thereof based on asymmetric carbon atoms (2) in the molecule.
EKSEMPEL 1 EXAMPLE 1
(1) I 50 ml dimetylsulfoksid inneholdende 590 mg kaliumhydroksid ble det oppløst 3,36 g (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-8-klor-2,3-dihydro-l,5-benzo-tiazepin-4(5H)-on, og oppløsningen ble omrørt ved romtemperatur i 30 minutter. Deretter ble det tilsatt 1,75 g l-klor-2-metansulfonyloksyetan til oppløsningen og blandingen ble omrørt ved romtemperatur. Etter at reaksjonen hadde gått til endes ble blandingen helt over i isvann og ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket og løsningsmidlet ble så destillert av. Etter at residuet var oppløst i eter og hadde stått, ble uløselige utgangsmaterialer fjernet ved filtrering. Filtratet ble inndampet for å fjerne løsningsmidlet. De oppnådde oljeaktige produktene ble renset kromatografisk i en silikagelkolonne (eluent: kloroform: etylacetat = 20 : 1), og rekrystallisert i etanol for å gi 1,05 g av en blanding (9 : 1) av (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-5-(2-kloretyl-8-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on og (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-5-[2-(metansulfonyloksy)etyl] -8-klor-2,3-dihydro-1,5-benzotiazepin-4(5H)-on. (1) In 50 ml of dimethyl sulfoxide containing 590 mg of potassium hydroxide, 3.36 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5- benzo-thiazepin-4(5H)-one, and the solution was stirred at room temperature for 30 minutes. Then 1.75 g of 1-chloro-2-methanesulfonyloxyethane was added to the solution and the mixture was stirred at room temperature. After the reaction had gone to completion, the mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was then distilled off. After the residue was dissolved in ether and stood, insoluble starting materials were removed by filtration. The filtrate was evaporated to remove the solvent. The oily products obtained were purified by chromatography on a silica gel column (eluent: chloroform: ethyl acetate = 20 : 1), and recrystallized in ethanol to give 1.05 g of a mixture (9 : 1) of (+)-cis-2- (4-Methoxyphenyl)-3-hydroxy-5-(2-chloroethyl-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and (+)-cis-2-(4 -methoxyphenyl)-3-hydroxy-5-[2-(methanesulfonyloxy)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Smeltepunkt 125 til 128°C. Melting point 125 to 128°C.
MS (m/e): 381, 379 (M<+> - CI^SO^ MS (m/e): 381, 379 (M<+> - Cl^SO^
(2) Dette produktet (1,03 g) ble løst i 10 ml dimetylformamid, og 900 mg av en 51% dimetylamin-toluen oppløsning ble tilsatt til løsningen og blandingen ble omrørt ved romtemperatur i 62 timer. Videre ble det tilsatt 180 mg av en 51% dimetylamin toluen oppløsning til blandingen og blandingen ble omrørt ved romtemperatur. Etter at reaksjonen hadde gått til endes ble det tilsatt vann til blandingen og blandingen ble ekstrahert med etylacetat. Ekstraktet ble vasket med vann og tørket, og deretter ble løsningsmidlet fjernet under redusert trykk. Residuet ble renset kromatografisk i en silikagelkolonne (eluent: kloroform : etanol = 95 : 5) og rekrystallisert fra et blandet løsningsmiddel av etylacetat og n-hexan for å gi 687 mg (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-5-[2-(dimetylamino)etyl]-8-klor-2,3-dihydro-1,5-benzotiazepin-4(5H)-on. (2) This product (1.03 g) was dissolved in 10 ml of dimethylformamide, and 900 mg of a 51% dimethylamine-toluene solution was added to the solution and the mixture was stirred at room temperature for 62 hours. Furthermore, 180 mg of a 51% dimethylamine toluene solution was added to the mixture and the mixture was stirred at room temperature. After the reaction had gone to completion, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and then the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform : ethanol = 95 : 5) and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 687 mg of (+)-cis-2-(4-methoxyphenyl)-3 -hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Smeltepunkt 122 til 124°C (dekomponerte). Melting point 122 to 124°C (decomposed).
EKSEMPEL 2 EXAMPLE 2
(1) I 150 ml dimetylsulfoksid inneholdende 1,77 g kaliumhydroksid ble det oppløst 10,08 g (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-8-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-oiBg)ppløsningen ble omrørt ved romtempertur i 30 minutter. Deretter ble det tilsatt 4,70 g l-brom-2-kloretan til oppløsningen og blandingen ble omrørt ved romtemperatur. Etter at reaksjonen hadde gått til endes, ble blandingen helt over i isvann og ekstrahert med etylacetat. Etter at ekstraktet var vasket med vann og tørket ble løsningsmidlet destillert av. Etter at residuet var oppløst i eter og hadde stått, ble utfelt utgangsmateriale fjernet ved filtrering. Filtratet ble inndampet ved å destillere av mesteparten av løsningsmidlet. Residuet fikk stå og utfelte krystaller ble skilt fra ved filtrering for å gi et råprodukt (5,94 mg). Filtratet ble kjørt gjennom en silikagel kromatografisk kolonne (eluent: kloroform : etylacetat = 20 : 1) og råproduktet fremstilt ble blandet med råproduktet fremstilt ovenfor, og de ble rekrystallisert fra etanol for å gi 7.94 g (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-5-(2-kloretyl)-8-klor-2,3-dihydro-l ,5-benzotiazepin-4(5H)-on. (1) In 150 ml of dimethyl sulfoxide containing 1.77 g of potassium hydroxide, 10.08 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1 were dissolved, The 5-benzothiazepine-4(5H)-oliBg) solution was stirred at room temperature for 30 minutes. Then 4.70 g of 1-bromo-2-chloroethane was added to the solution and the mixture was stirred at room temperature. After the reaction had gone to completion, the mixture was poured into ice water and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. After the residue had been dissolved in ether and had stood, precipitated starting material was removed by filtration. The filtrate was evaporated by distilling off most of the solvent. The residue was allowed to stand and precipitated crystals were separated by filtration to give a crude product (5.94 mg). The filtrate was passed through a silica gel chromatographic column (eluent: chloroform : ethyl acetate = 20 : 1) and the crude product prepared was mixed with the crude product prepared above, and they were recrystallized from ethanol to give 7.94 g of (+)-cis-2-(4 -methoxyphenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.
Smeltepunkt 128 til 131°C. Melting point 128 to 131°C.
IR<N>ui°Lx (cm<1>): 3460, 1660, 1590. IR<N>ui°Lx (cm<1>): 3460, 1660, 1590.
MS (m/e): 399, 397 (M<+>). (2) Dette produktet, en 51% dimetylamin-toluen oppløsning og dimetylformamid ble bragt til å reagere og berabeidet på samme måte som beskrevet i eksempel l-(2) for å gi (+)-cis-2-(4-metolayfenyl)-3-hydroksy-5-(dimetylamino)etyl]-8-klor-2,3-dmydro-l,5-benzotiazepin-4(5H)-on. MS (m/e): 399, 397 (M<+>). (2) This product, a 51% dimethylamine-toluene solution and dimethylformamide were reacted and worked up in the same manner as described in Example 1-(2) to give (+)-cis-2-(4-metholayphenyl) -3-hydroxy-5-(dimethylamino)ethyl]-8-chloro-2,3-dimethylhydro-1,5-benzothiazepin-4(5H)-one.
Smeltepunkt 122 til 124°C (dekomponerte). Melting point 122 to 124°C (decomposed).
EKSEMPEL 3 EXAMPLE 3
(1) Til en blanding av 3 ml edikksyreanhydrid og 2 ml edikksyre ble det tilsatt 484 mg (+)-cis-2-(4-metoksy-fenyl)-3-hydroksy-5-(2-kloretyl)-8-klor-2,3-dmydro-l,5-benzotiazepin-4(5H)-on og blandingen ble omrørt ved 110°C. Etter at reaksjonen hadde gått til endes ble blandingen inndampet under redusert trykk for å destillere av løsningsmidlet. Etter at residuet var oppløst i toluen, ble det inndampet til det var tørt under redusert trykk for å gi 535 mg (+)-cis-2-(4-metoksyfenyl)-3-acetoksy-5-(2-kloretyl)-8-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on som et oljeaktigt produkt. (1) To a mixture of 3 ml of acetic anhydride and 2 ml of acetic acid was added 484 mg of (+)-cis-2-(4-methoxy-phenyl)-3-hydroxy-5-(2-chloroethyl)-8-chloro -2,3-dihydro-1,5-benzothiazepin-4(5H)-one and the mixture was stirred at 110°C. After the reaction had gone to completion, the mixture was evaporated under reduced pressure to distill off the solvent. After the residue was dissolved in toluene, it was evaporated to dryness under reduced pressure to give 535 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-chloroethyl)-8 -chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one as an oily product.
IR""^ (cm"<1>): 1740, 1680, 1600, 1580. IR""^ (cm"<1>): 1740, 1680, 1600, 1580.
MS (m/e): 439, 441 (M<+>). (2) Dette produktet, en 51 % dimetylamin-toluen oppløsning og dimetylformamid ble bragt til å reagere og ble bearbeidet på samme måte som beskrevet i eksempel l-(2) for å gi (+)-cis-2-(4-metoksyfenyl)-3-acetoksy-5-[2-(dimetylamino)etyl]-8-klor-2,3Kiihydro-l,5-benzotiazepin-4-(5H)-on. MS (m/e): 439, 441 (M<+>). (2) This product, a 51% dimethylamine-toluene solution and dimethylformamide were reacted and worked up in the same manner as described in Example 1-(2) to give (+)-cis-2-(4-methoxyphenyl) )-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3Kihydro-1,5-benzothiazepin-4-(5H)-one.
Maleat av dette produktet: Maleate of this product:
Smeltepunkt 158 til 160°C (rekrystallisert fra etanol). Melting point 158 to 160°C (recrystallized from ethanol).
EKSEMPLENE 4 og 5 EXAMPLES 4 and 5
Ved å behandle tilsvarende utgangsmateriale på samme måte som i eksemplene 1 til 3, kan følgende forbindelser fremstilles. (4) (+)-cis-2-(4-metoksyfenyl)-3-hydroksy-5-[2-(dimetylamino)etyl]-9-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on.perklorat.l/4 hydrat. By treating the corresponding starting material in the same way as in Examples 1 to 3, the following compounds can be prepared. (4) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepine-4( 5H)-one.perchlorate.l/4 hydrate.
Smeltepunkt 190 til 192°C. Melting point 190 to 192°C.
(5) (+)-cis-2-(4-metoksyfenyl-3-acetoksy-5-[2-(dimetylamino)etyl]-9-klor-2,3-dihydro-l,5-benzotiazepin-4(5H)-on.hydroklorid.monohydrat. (5) (+)-cis-2-(4-methoxyphenyl-3-acetoxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H )-on.hydrochloride.monohydrate.
Smeltepunkt 140 til 143°C. Melting point 140 to 143°C.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO922253A NO172286C (en) | 1987-08-12 | 1992-06-09 | PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62202027A JPS6445376A (en) | 1987-08-12 | 1987-08-12 | Production of 1,5-benzothiazepine derivative |
| NO883525A NO170017C (en) | 1987-08-12 | 1988-08-09 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1,5-BENZOTIAZEPINE DERIVATIVES |
| NO922253A NO172286C (en) | 1987-08-12 | 1992-06-09 | PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO922253L NO922253L (en) | 1989-02-13 |
| NO922253D0 NO922253D0 (en) | 1992-06-09 |
| NO172286B true NO172286B (en) | 1993-03-22 |
| NO172286C NO172286C (en) | 1993-06-30 |
Family
ID=27328032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO922253A NO172286C (en) | 1987-08-12 | 1992-06-09 | PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTIAZEPINE DERIVATIVES |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO172286C (en) |
-
1992
- 1992-06-09 NO NO922253A patent/NO172286C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO172286C (en) | 1993-06-30 |
| NO922253D0 (en) | 1992-06-09 |
| NO922253L (en) | 1989-02-13 |
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