NO161672B - PROCEDURE FOR PREPARING A CYANETYLERTED 3-HYDROXY-1,4-BENZODIAZEPIN-2-ON DERIVATE. - Google Patents
PROCEDURE FOR PREPARING A CYANETYLERTED 3-HYDROXY-1,4-BENZODIAZEPIN-2-ON DERIVATE. Download PDFInfo
- Publication number
- NO161672B NO161672B NO850189A NO850189A NO161672B NO 161672 B NO161672 B NO 161672B NO 850189 A NO850189 A NO 850189A NO 850189 A NO850189 A NO 850189A NO 161672 B NO161672 B NO 161672B
- Authority
- NO
- Norway
- Prior art keywords
- hydroxy
- benzodiazepine
- acyl
- formula
- cyanetylerted
- Prior art date
Links
- YSPYFFRTSUIPCB-UHFFFAOYSA-N 1h-1,4-benzodiazepine-2,3-dione Chemical compound N1C(=O)C(=O)N=CC2=CC=CC=C21 YSPYFFRTSUIPCB-UHFFFAOYSA-N 0.000 title claims description 4
- 238000000034 method Methods 0.000 title claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000000543 intermediate Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000007278 cyanoethylation reaction Methods 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- -1 1-(2-cyanoethyl) -7-chloro-3-acetoxy-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one Chemical compound 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 2
- XAXMYHMKTCNRRZ-UHFFFAOYSA-N cinolazepam Chemical compound C12=CC(Cl)=CC=C2N(CCC#N)C(=O)C(O)N=C1C1=CC=CC=C1F XAXMYHMKTCNRRZ-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical group N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ZQGZUOLMBIKREL-UHFFFAOYSA-N [7-chloro-5-(2-fluorophenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl] acetate Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(OC(=O)C)N=C1C1=CC=CC=C1F ZQGZUOLMBIKREL-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 125000003310 benzodiazepinyl group Chemical group N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av et cyanetylert 3-hydroksy-l,4-benzodiazepin-2-on-derivat, som oppviser terapeutiske fordeler som sovemiddel, sammenlignet med lignende preparater. This invention relates to a process for the preparation of a cyanoethylated 3-hydroxy-1,4-benzodiazepine-2-one derivative, which exhibits therapeutic advantages as a sleeping aid, compared to similar preparations.
En forbindelse med formelen fremstilles ifølge AT-PS 361 492 ved selektiv cyanetylering av et 3-hydroksy-l,4-benzodiazepin-2-on-derivat med formelen A compound of the formula is prepared according to AT-PS 361 492 by selective cyanoethylation of a 3-hydroxy-1,4-benzodiazepine-2-one derivative of the formula
Selektiviteten av substitusjonen av NH-gruppen begunstiges her ved tilsetning av fase-overføringskatalysatorer som f.eks. trietylbenzylammoniumklorid. Uten denne forholdsvis dyre tilsetning skjer det også en cyanoetylering på OH-gruppen, hvorved det blir nødvendig med en separering av mono- og disubstitusjons-produkt, og man får et redusert utbytte. The selectivity of the substitution of the NH group is favored here by the addition of phase-transfer catalysts such as e.g. triethylbenzylammonium chloride. Without this relatively expensive addition, a cyanoethylation also takes place on the OH group, whereby a separation of mono- and di-substitution product becomes necessary, and a reduced yield is obtained.
Utgangsforbindelsene med formel II fremstilles hovedsakelig ifølge Journ. Org. Chem. 27,1691 (1962) ved forsepning av de tilsvarende O-Acyl-forstadier med den generelle formel III The starting compounds of formula II are prepared mainly according to Journ. Org. Chem. 27,1691 (1962) by saponification of the corresponding O-Acyl precursors with the general formula III
hvor where
Acyl betyr en virkårlig acylrest, hvor 3-stillingen er beskyttet mot en cyanetylering ved hjelp av acylresten. Acyl means an arbitrary acyl residue, where the 3-position is protected against cyanoethylation by means of the acyl residue.
Ifølge oppfinnelsen kan nu forbindelsen med formel I fremstilles direkte fra dette O-Acyl-forstadium III ved et et-kars prosess, ved at man omsetter O-Acyl-derivatene III uten anvendelse av en fase-overføringskatalysator, med en forbindelse med formelen According to the invention, the compound of formula I can now be prepared directly from this O-Acyl precursor III in a one-pot process, by reacting the O-Acyl derivatives III without the use of a phase-transfer catalyst, with a compound of the formula
i basisk miljø, og de nye mellomprodukter med den generelle formel in basic environment, and the new intermediates with the general formula
hvor where
Acyl har den ovenfor angitte betydning, forsepes alkalisk direkte. Forbindelsene med den generelle formel I oppnås derved i godt utbytte ved en forenklet fremgangsmåte. Acyl has the meaning given above, saponified alkaline directly. The compounds of the general formula I are thereby obtained in good yield by a simplified method.
Forbindelsene med formel V er nye, og ved forsepningen underkastes de en selektiv hydrolyse av acyloksy-gruppen i nærvær av en CN-gruppe som forblir intakt. Dessuten angripes heller ikke det alkali-ømfindtlige benzodiazepin-ringsystem. Det er således dobbelt overraskende at under de anvendte reaksjonsbetingelser blir acyloksy-gruppen hydrolysert selektivt og med høyt utbytte uten at de to i og for seg hydrolyserbare grupperinger (henholdsvis CN og benzodiazepin-ringen) samtidig reagerer. The compounds of formula V are new, and during the saponification they are subjected to a selective hydrolysis of the acyloxy group in the presence of a CN group which remains intact. Moreover, the alkali-sensitive benzodiazepine ring system is not attacked either. It is therefore doubly surprising that under the reaction conditions used, the acyloxy group is hydrolysed selectively and with high yield without the two inherently hydrolyzable groupings (respectively CN and the benzodiazepine ring) reacting at the same time.
Det følgende eksempel illustrerer oppfinnelsen ytterligere. Temperaturangivelser er i grader Celsius. The following example further illustrates the invention. Temperature indications are in degrees Celsius.
EKSEMPEL EXAMPLE
En suspensjon av 5 g 7-klor-3-acetoksy-5-(2'-fluor-fenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on i 20 ml aceton og 10 ml destillert vann tilsettes dråpevis ved romtemperatur 1 ml akrylnitril og derefter dråpevis 3 ml IN NaOH. En prøve av blandingen som er omrørt natten over, viser på tynnsjiktkromatogram (silikagel 60F254, utviklingsmiddel: toluen/etanol/NH4OH, 25%ig = 70:30:1,5) en praktisk talt fullstendig omsetning til 1-(2-cyanetyl)-7-klor-3-acetoksy-5-(2'-fluor-fenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on, hvorav allerede en liten del er forsepet til 1-(2-cyanetyl)-7-klor-3-hydroksy-5-(2'-fluor-fenyl) -1,3-dihydro-2H-l,4-benzodiazepin-2-on. A suspension of 5 g of 7-chloro-3-acetoxy-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 20 ml of acetone and 10 ml of distilled water add dropwise at room temperature 1 ml of acrylonitrile and then dropwise 3 ml of IN NaOH. A sample of the mixture stirred overnight shows on a thin-layer chromatogram (silica gel 60F254, developer: toluene/ethanol/NH4OH, 25%ig = 70:30:1.5) a practically complete conversion to 1-(2-cyanoethyl) -7-chloro-3-acetoxy-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, of which a small part is already saponified to 1-(2 -cyanoethyl)-7-chloro-3-hydroxy-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one.
Ved dråpevis tilsetning av 14 ml IN NaOH til blandingen som omrøres ved romtemperatur, gjøres forsepningen fullstendig i løpet av 5 timer. Derefter tilsetter man dråpevis litt efter litt 16 ml IN HC1, omrører i ytterligere 1 time, lar blandingen stå natten over ved 4°, avsuger og eftervasker med vann og isopropanol. By dropwise addition of 14 ml of 1N NaOH to the mixture which is stirred at room temperature, the saponification is complete within 5 hours. 16 ml of IN HC1 are then added drop by drop, stirred for a further 1 hour, the mixture is allowed to stand overnight at 4°, aspirated and washed with water and isopropanol.
Det således oppnådde 1-(2-cyanetyl)-7-klor-3-hydroksy-5-(2'-fluor-fenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on veier efter tørking 4,8 g (93% av det teoretiske) og smelter efter omkrystallisering fra aceton eller metanol ved 190-193°. The thus obtained 1-(2-cyanoethyl)-7-chloro-3-hydroxy-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one weighs after drying 4.8 g (93% of the theoretical) and melts after recrystallization from acetone or methanol at 190-193°.
Det cyanetylerte mellomprodukt kan f.eks. fremstilles i ren form på følgende måte: Til en omrørt suspensjon av 5 g 7-klor-3-acetoksy-5- The cyanoethylated intermediate can e.g. is prepared in pure form as follows: To a stirred suspension of 5 g of 7-chloro-3-acetoxy-5-
(2'-fluor-fenyl)-1, 3-dihydro-2H-l,4-benzodiazepin-2-on- i 20 ml akrylnitril setter man 2 dråper av en 40%ig metanolisk oppløsning av benzyltrimetyl-ammoniumhydroksyd ("Triton B"-oppløsning). En prøve av blandingen som er omrørt natten over, viser på tynnsjiktkromatogram (silikagel 60F254, utviklingsmiddel: kloroform/metanol = 9:1) praktisk talt fullstendig omsetning til 1-(2-cyanetyl)-7-klor-3-acetoksy-5-(2'fluor-fenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on. Man fortynner suspen-sjonen med petroleter, lar det hele stå i noen timer ved 4°, avsuger og vasker med noe isopropanol. Utbytte: 5,4g (93,7%). Efter omkrystalliseringen fra metanol smelter produktet ved 200-202 0 . (2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-in 20 ml of acrylonitrile, 2 drops of a 40% methanolic solution of benzyltrimethylammonium hydroxide ("Triton B " resolution). A sample of the mixture stirred overnight shows on a thin-layer chromatogram (silica gel 60F254, developer: chloroform/methanol = 9:1) practically complete conversion to 1-(2-cyanoethyl)-7-chloro-3-acetoxy-5- (2'Fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one. The suspension is diluted with petroleum ether, the whole is allowed to stand for a few hours at 4°, aspirated and washed with some isopropanol. Yield: 5.4g (93.7%). After the recrystallization from methanol, the product melts at 200-202 0 .
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0015084A AT379391B (en) | 1984-01-18 | 1984-01-18 | METHOD FOR PRODUCING CYANAETHYLATED BENZODIAZEPINE |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO850189L NO850189L (en) | 1985-07-19 |
| NO161672B true NO161672B (en) | 1989-06-05 |
| NO161672C NO161672C (en) | 1989-09-13 |
Family
ID=3482860
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO850189A NO161672C (en) | 1984-01-18 | 1985-01-17 | PROCEDURE TE FOR PREPARING A CYANETYLERTED 3-Y-1,4-BENZODIAZEPIN-2-ON DERIVATE. |
Country Status (6)
| Country | Link |
|---|---|
| KR (1) | KR910006989B1 (en) |
| AT (1) | AT379391B (en) |
| ES (1) | ES8601929A1 (en) |
| NO (1) | NO161672C (en) |
| NZ (1) | NZ210740A (en) |
| PT (1) | PT79831B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101923058B1 (en) * | 2012-04-30 | 2019-02-20 | 김영진 | High dielectric polymer composite composition and energy storage device using same |
-
1984
- 1984-01-18 AT AT0015084A patent/AT379391B/en not_active IP Right Cessation
- 1984-12-26 ES ES539059A patent/ES8601929A1/en not_active Expired
-
1985
- 1985-01-04 NZ NZ210740A patent/NZ210740A/en unknown
- 1985-01-14 KR KR1019850000199A patent/KR910006989B1/en not_active IP Right Cessation
- 1985-01-16 PT PT79831A patent/PT79831B/en not_active IP Right Cessation
- 1985-01-17 NO NO850189A patent/NO161672C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AT379391B (en) | 1985-12-27 |
| ATA15084A (en) | 1984-11-15 |
| ES539059A0 (en) | 1985-11-16 |
| KR850005420A (en) | 1985-08-26 |
| PT79831A (en) | 1985-02-01 |
| NZ210740A (en) | 1987-07-31 |
| PT79831B (en) | 1986-10-28 |
| ES8601929A1 (en) | 1985-11-16 |
| KR910006989B1 (en) | 1991-09-14 |
| NO161672C (en) | 1989-09-13 |
| NO850189L (en) | 1985-07-19 |
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