8-Chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (Alprazolam) by Asch

Query Query

Results

Date

25 reactions in Reaxys

2017-08-03 07h:49m:24s (EST)

25 reactions in Reaxys

2017-08-03 08h:23m:59s (EST)

1. Query

N N N

Search as: As drawn 2. Query

LAST_RESULT AND itemno in (1,2,3)

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N O

N N

Rx-ID: 3252290 View in Reaxys 1/25 Yield

Conditions & References

59 %

With hydrazine hydrate in ethanol, 1) room temp., 2.5 h ; 2) 63 deg C, 3 h . Hester Jr.; Journal of Heterocyclic Chemistry; vol. 17; nb. 3; (1980); p. 575 - 581 View in Reaxys 5 : 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine EXAMPLE 5 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine A stirred mixture of 5-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (0.257 g., 0.562 mmole) and absolute ethanol (3 ml.) was treated with hydrazine hydrate (0.05 ml., 1.04 mmole) and warmed in an oil bath at 73° C. for 80 minutes. (The solution precipitated a white solid after 30 minutes.) The cooled mixture was mixed with water and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel (42 g.) with 2percent methanol-98percent chloroform; 10 ml. fractions were collected. The product was eluted in fractions 33-57 and crystallized from ethyl acetate to give 77 mg., of melting point 229°-230° C. and 26 mg., of melting point 228°-229.5° C. of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Anal. calcd. for C17 H13 ClN4: C, 66.13; H, 4.24; Cl, 11.48; N, 18.15. Found: C, 66.05; H, 4.13; Cl, 11.34; N, 18.00. With hydrazine hydrate in ethanol Patent; The Upjohn Company; US3993660; (1976); (A1) English View in Reaxys

H+

N N

N H 2N

Rx-ID: 3618156 View in Reaxys 2/25 Yield

Conditions & References in water, T= 25 °C , pH 2.0-8.5, Rate constant, Equilibrium constant Cho; Scahill; Hester Jr.; Journal of Pharmaceutical Sciences; vol. 72; nb. 4; (1983); p. 356 - 362 View in Reaxys

N Br

Rx-ID: 3779005 View in Reaxys 3/25 Yield 83.3 %

Conditions & References With ammonia in dichloromethane, 1) -50 deg C , 2) reflux 5 h

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Hester Jr.; Journal of Heterocyclic Chemistry; vol. 17; nb. 3; (1980); p. 575 - 581 View in Reaxys 10 : 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine EXAMPLE 10 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (391 mg., 0.001 mole) in tetrahydrofuran (15 ml.) is cooled in an ice bath and treated with a saturated solution of ammonia in methanol (12.5 ml.). The resulting solution is allowed to warm to ambient temperature and stand for 24 hours. It is then concentrated in vacuo. The residue is suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract is washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue is crystallized from methylene chloride-ethyl acetate to give 0.229 g. of crude product of melting point 227°-228.5° C. Recrystallization of this material from ethyl acetate gives three crops of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3a][1,4]benzodiazepine: 0.142 g. of melting point 228°-229.5°, 0.053 g. of melting point 228.5°-229.5° C. and 0.021 g. of melting point 228°-229.5° C. With ammonia, sodium hydrogencarbonate in tetrahydrofuran, methanol, water, ethyl acetate Patent; The Upjohn Company; US4000151; (1976); (A1) English View in Reaxys Cl

N N

Rx-ID: 6406430 View in Reaxys 4/25 Yield 98%

Conditions & References 11 : EXAMPLE 11 EXAMPLE 11 To a solution of 0.1 part of 5-chloro-2-(4-hydroxyaminomethyl-1-methyl-s-triazol-4-yl) benzophenone in 1 volume part of methanol is added one drop of concentrated hydrochloric acid, followed by keeping standing for 10 minutes at room temperature. The resultant is neutralized with a saturated aqueous solution of sodium bicarbonate, whereby crystals of 8-chloro-1methyl-6-phenyl-4H-s-triazolo(4,3-a)(1,4) benzodiazepine 5N-oxide are obtained. Recrystallization of the crystals from methanol gives colorless needles melting at 271° to 272° C (decomposition). Yield: 98percent. The infrared absorption spectrum of the product is identical with that of the product obtained in example 10. Patent; Takeda Chemical Industries, Ltd.; US4082764; (1978); (A1) English View in Reaxys Acethydrazid,7-Chlor-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-thion(28) Hester Jr.; Rudzik; Kamdar; Journal of medicinal chemistry; vol. 14; nb. 11; (1971); p. 1078 - 1081 View in Reaxys Essigsaeure 2-(5-phenyl-7-chlor-3H-1,4-benzodiazepin-2-yl)hydrazid(18),Δ Hester Jr.; Rudzik; Kamdar; Journal of medicinal chemistry; vol. 14; nb. 11; (1971); p. 1078 - 1081 View in Reaxys Hydrazinobenzodiazepin(VIa),CH3C(OEt)3,H2SO4 Meguro et al.; Chemical and Pharmaceutical Bulletin; vol. 21; (1973); p. 2382,2387 View in Reaxys 2-(2-Acetylhydrazino)-7-chlor-5-phenyl-3H-1,4-benzodiazepin,Pyridin

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Meguro et al.; Chemical and Pharmaceutical Bulletin; vol. 21; (1973); p. 2382,2387 View in Reaxys Hydrazinobenzodiazepin(VIa),Acetamidin*HCl,2-Methylimidazol Meguro et al.; Chemical and Pharmaceutical Bulletin; vol. 21; (1973); p. 2382,2387 View in Reaxys Hydrazinobenzodiazepin(VIa),Ac2O,H2SO4 Meguro et al.; Chemical and Pharmaceutical Bulletin; vol. 21; (1973); p. 2382,2387 View in Reaxys 2-<2-(2-Amino)ethylidenhydrazino>-7-chlor-5-phenyl-3H-1,4-benzodiazepin,200grad Meguro et al.; Chemical and Pharmaceutical Bulletin; vol. 21; (1973); p. 2382,2387 View in Reaxys Hydrazinobenzodiazepin(VIa),Ethylacetimidat*HCl Meguro et al.; Chemical and Pharmaceutical Bulletin; vol. 21; (1973); p. 2382,2387 View in Reaxys 2-(2-Acetylhydrazino)-7-chlor-5-phenyl-3H-1,4-benzodiazepin (1A) durch Erhitzen oder 7-Chlor-5-phenyl-DHBDA-thion, Essigsaeurehydrazid in A direkt (Beispiel 2) Patent; Upjohn Co.; DE2012190; (1970); ; vol. 73; nb. 10980i View in Reaxys Thiolactam XII, Ac2O Hesters,J.B. et al.; Tetrahedron Letters; (1971); p. 1609 - 1612 View in Reaxys 6,Acetanhydrid Ning,R.Y. et al.; Journal of Organic Chemistry; vol. 41; (1976); p. 2724 - 2727 View in Reaxys 1,NaH Ning,R.Y. et al.; Journal of Organic Chemistry; vol. 41; (1976); p. 2724 - 2727 View in Reaxys 16,Acetanhydrid Ning,R.Y. et al.; Journal of Organic Chemistry; vol. 41; (1976); p. 2724 - 2727 View in Reaxys a) Benzophenon 7 (S.8), CH3SO2Cl/NH3; b) Benzophenon 3 (S. 13), N2H4 Patent; Upjohn Co.; FR2217335; (1974); DE2402363; ; vol. 81; nb. 152289 View in Reaxys /BRN= 165715/ in siedendem Butanol Patent; Hoffmann-LaRoche; US3864328; (1975); ; vol. 82; nb. 171107 View in Reaxys /BRN= 762127/,NH3 Meguro; Tawada; Kuwada; Chemical and Pharmaceutical Bulletin; vol. 21; nb. 7; (1973); p. 1619 - 1621 View in Reaxys /BRN= 762127/,Urotropin Meguro; Tawada; Kuwada; Chemical and Pharmaceutical Bulletin; vol. 21; nb. 7; (1973); p. 1619 - 1621 View in Reaxys

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aus 2-(2-Acetylhydrazino)-7-chlor-5-phenyl-3H-1,4-benzodiazepin Patent; The Upjohn Company; US3701782; (1972); DE2065893; ; vol. 85; nb. 192782 View in Reaxys 2-NHNH2-Benzdiazepin, CH3CH(OEt)3 Patent; Takeda; DE2114441; (1971); ; vol. 76; nb. 34321; (1972) View in Reaxys 2-NHNHCOCH3-Benzdiazepin Patent; Takeda; DE2114441; (1971); ; vol. 76; nb. 34321; (1972) View in Reaxys Benzodiazepin 2a,/BRN= 908662/ Walser; Zenchoff; Journal of Medicinal Chemistry; vol. 20; nb. 12; (1977); p. 1694 - 1697 View in Reaxys 2b,Umlagerung mit NEt3/Butanol Walser; Zenchoff; Journal of Heterocyclic Chemistry; vol. 15; nb. 1; (1978); p. 161 - 163 View in Reaxys 7-Chlor-2-<bis(morpholino)phosphinyloxy>-5-phenyl-3H-1,4-benzodiazepin/Acethydrazid Patent; Hoffmann-La Roche and Co.; FR2293437; (1976); DE2540586; (1976); ; vol. 85; nb. 33094 View in Reaxys Diazepin 16, NaOH Hester,J.B.; Von Voigtlander,P.; Journal of Medicinal Chemistry; vol. 22; (1979); p. 1390 - 1398 View in Reaxys Benzodiazepin 13, Erhitzen/Luft Hester; Jr. et al.; Journal of Organic Chemistry; vol. 44; (1979); p. 2688,2692 View in Reaxys Cyclisierung d. diazepins (Bsp. 1) Patent; The Upjohn Co.; DE2242938; (1973); ; vol. 78; nb. 159693 View in Reaxys a) Halogenmethylvbg. (Praep. 10-12), NH3 (3); b) 5,5-Dihydrovbg. (Praep.) durch Oxid. (18) Patent; The Upjohn Co.; DE2242918; (1973); ; vol. 78; nb. 159694 View in Reaxys 7-Chlor-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-thion,Acetylchlorid Patent; Upjohn; US28505; (1975); ; vol. 84; nb. 17443 View in Reaxys 5-Chloro-2-<3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl>benzophenon, NH3 Patent; Upjohn; US3903103; (1975); ; vol. 84; nb. 31146 View in Reaxys 24,Acetylhydrazid Coffen; DeNoble; Evans; et al.; Journal of Organic Chemistry; vol. 39; nb. 2; (1974); p. 167 - 172 View in Reaxys 1) Entspr. Thion, Acetohydrazid 2) Erhitzen Patent; Upjohn Co.; US3681343; (1971); ; vol. 77; nb. 126707

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View in Reaxys entspr.Triazolylbenzophenon Patent; Upjohn; DE2601400; (1976); ; vol. 86; nb. 29899 View in Reaxys Benzophenon 32 Patent; Upjohn; DE2240198; (1972); ; vol. 78; nb. 136354 View in Reaxys 5,6-Dihydroverb.,Diethylazodicarboxylat Patent; Upjohn Co.; US3772317; (1971); ; vol. 80; nb. 59944 View in Reaxys Patent; Upjohn Co.,; DE2221790; (1972); ; vol. 78; nb. 72232 View in Reaxys aus 2-(2-Acetyl-hydrazin-7-chloro-5-phenyl-3H-1,4-benzodiazepin (Bsp. 25), Δ Patent; Takeda Chem. Ind. Ltd.; DE1955349; (1971); ; vol. 74; nb. 88078 View in Reaxys aus 2-(2-Acetyl-hydrazin-7-chloro-5-phenyl-3H-1,4-benzodiazepin (Bsp. 25), Δ, Py Patent; Takeda Chem. Ind. Ltd.; DE1955349; (1971); ; vol. 74; nb. 88078 View in Reaxys 8-Chlor-1-methyl-6-phenyl-4H-s-triazolo-<4,3-a><1,4>-benzodiazepin-4-carbonsaeure-ethylester/NaOH Patent; Upjohn Co.; CH569736; (1975); DE2203782; ; vol. 77; nb. 126708 View in Reaxys 5-Chlor-2-<3-(brommethyl)-5-methyl-4H-1,2,4-triazol-4-yl>-benzophenon/NH3 Patent; Upjohn Co.; CH569736; (1975); DE2203782; ; vol. 77; nb. 126708 View in Reaxys 8-Chlor-5,6-dihydro-1-methyl-6-phenyl-4H-s-triazolo<4,3a><1,4>benzodiazepin/Diethyl-azo-dicarboxylat Patent; Upjohn Co.; CH569736; (1975); DE2203782; ; vol. 77; nb. 126708 View in Reaxys aus 2-Amino-7-chloro-5-phenyl-3H-1,4-benzodiazepin, N2H4*H2O, 2-Methyl-imidazol*HCl, MeC(OEt)3 Patent; Takeda Chem. Ind. Ltd.; DE1955349; (1971); ; vol. 74; nb. 88078 View in Reaxys aus 7-Chloro-2-hydrazin-5-phenyl-3H-1,4-benzodiazepin, MeC(OEt)3, TsOH Patent; Takeda Chem. Ind. Ltd.; DE1955349; (1971); ; vol. 74; nb. 88078 View in Reaxys aus 7-Chloro-2-hydrazin-5-phenyl-3H-1,4-benzodiazepin, Ac2O, konz. H2SO4 Patent; Takeda Chem. Ind. Ltd.; DE1955349; (1971); ; vol. 74; nb. 88078 View in Reaxys aus 7-Chloro-2-hydrazin-5-phenyl-3H-1,4-benzodiazepin, Ethylacetoimidat*HCl/2-Methyl-imidazol Patent; Takeda Chem. Ind. Ltd.; DE1955349; (1971); ; vol. 74; nb. 88078 View in Reaxys aus 7-Chloro-2-hydrazin-5-phenyl-3H-1,4-benzodiazepin, Acetamidin*HCl/2-Methyl-imidazol Patent; Takeda Chem. Ind. Ltd.; DE1955349; (1971); ; vol. 74; nb. 88078 View in Reaxys

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aus 2-(α-Aminoethylidene)-hydrazin-7-chloro-5-phenyl-3H-1,4-benzodiazepin (Bsp. 23), Δ Patent; Takeda Chem. Ind. Ltd.; DE1955349; (1971); ; vol. 74; nb. 88078 View in Reaxys 7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. in water, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English View in Reaxys 7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. With 2-hydroxypropyl-β-CD in ethanol, water, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English

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View in Reaxys 7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. With 2-hydroxypropyl-β-CD in water, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English View in Reaxys 7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. With 2-hydroxypropyl-β-CD in water, dimethyl sulfoxide, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English View in Reaxys

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7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. With sulfobutyl ether β-cyclodextrin in ethanol, water, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English View in Reaxys 7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. With sulfobutyl ether β-cyclodextrin in water, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English View in Reaxys 7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hy-

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drochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. With sulfobutyl ether β-cyclodextrin in water, dimethyl sulfoxide, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English View in Reaxys 7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. in ethanol, water, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English View in Reaxys 7 :The effect of cyclodextrins and organic solvents on the rate of diazepine ring-closure of several selected benzodiazepines was investigated. Stock solutions containing 1.0.x.10-3 M of the benzodiazepine in 0.10 M aqueous hydrochloric acid solution (pH approx. 1.1) were prepared and stored at 37.0° C. The benzodiazepines were in the ring-open form in these stock solutions. Aqueous 0.50 M tris buffer (pH 7.50) solution was prepared. The observed first-order rate constant for the closing (i.e. formation) of the benzodiazepine ring was determined in the following

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reaction media: a) pure aqueous tris buffer solution; b) aqueous tris buffer solution containing 10percent (w/v) cyclodextrin; c) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) ethanol (EtOH); d) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (v/v) EtOH; e) tris buffer solution containing 10percent (w/v) cyclodextrin and 10percent (v/v) dimethylsulfoxide (DMSO); and f) tris buffer solution containing 10percent (w/v) cyclodextrin and 50percent (w/v) DMSO. The stock solution (30 μl) was added to 1.50 ml of the reaction media which had previously been equilibrated to 37.0° C. and the first-order rate constant for the appearance of the closed form determined from the appearance of the closed form as observed on HPLC. Tables 5, 6 and 7 show the effects of cyclodextrins, EtOH and DMSO on the observed first-order rate constant for the regeneration of alprazolam, triazolam and midazolam, respectively. In pure aqueous buffer solutions, addition of EtOH and DMSO decreases somewhat the rate of ring closure, at least in the case of alprazolam and midazolam. Addition of cyclodextrin or the organic solvents have insignificant effect on the pH under these conditions. The dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring closure. The cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin. Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form. EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation. in water, dimethyl sulfoxide, pH= 7.50, Rate constant Patent; Cyclops, ehf.; US6699849; (2004); (B1) English View in Reaxys Following the procedure of the preceding examples 1 to 4, inclusive, animal feeds are similarly prepared, substituting equimolar amounts of: 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine 8-Chloro-1-methyl-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine 8-Chloro-1-methyl-6-(o-fluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine 1-Methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 8-Chloro-1-propyl-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine 8-Chloro-1-isopropyl-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine 8-Chloro-1,6-diphenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine 1-Benzyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine ... Patent; The Upjohn Company; US4000289; (1976); (A1) English View in Reaxys 19 : EXAMPLE 19 After evaporation of the solvent, the residue is treated in a similar manner to Example 18 to give 8-chloro-1-methyl-6phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine as colorless needles. Melting point: 224° C to 225° C. Thus obtained product is identical with the product prepared in Example 18. Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys 59 : EXAMPLE 59 EXAMPLE 59 To a solution of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3,4-1,4-benzodiazepine 4N-oxide in 100 parts by volume of ethanol, is added 2.5 parts of ethyl acetoimidate hydrochloride. The mixture is refluxed for about 30 minutes, followed by evaporation of the solvent. The residue is neutralized with a saturated aqueous solution of sodium bicarbonated, whereby 8-chloro-1-methyl-6phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine 5N-oxide is obtained as crystals. Recrystallization from a mixture of methanol and diethyl ether yields colorless needles melting at 268° C to 269° C. (decomposition). Thus obtained product is identical with the product prepared in Example 58. Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys

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The use according to claim 1 or 2, characterized in that the compound of formula Ia or Ib is selected from 8-chloro-1-methyl-6-phenyl-4 H -s-triazolo[4,3-a][1,4]benzodiazepine, 8-chloro-1-methyl-6-(o-fluorophenyl)-4 H -s-triazolo[4,3-a][1,4]benzodiazepine, 1-methyl-6-phenyl-4 H -s-triazolo[4,3-a][1,4]benzodiazepine, 8-chloro-1-propyl-6-phenyl-4 H -s-triazolo[4,3-a]-[1,4]benzodiazepine, 8-chloro-1-isopropyl-6-phenyl-4 H -s-triazolo[4,3-a][1,4]benzodiazepine, ... Patent; SCHERING CORPORATION; EP345931; (1989); (A1) English View in Reaxys

O N

H N

NH 2

N N

Rx-ID: 10311359 View in Reaxys 5/25 Yield

Conditions & References

87 %

With toluene-4-sulfonic acid in N,N-dimethyl-formamide, Time= 1h, T= 120 °C Fustero, Santos; Gonzalez, Javier; Del Pozo, Carlos; Molecules; vol. 11; nb. 8; (2006); p. 583 - 588 View in Reaxys Cl

2-hydroxypropyl-beta-cyclodextrin

N N

Rx-ID: 10730222 View in Reaxys 6/25 Yield

Conditions & References 5 : EXAMPLE 5 EXAMPLE 5 A pre-mixture of alprazolam (3.87 g) and 2-hydroxypropyl-beta cyclodextrin (150 g) was prepared by geometric dilution in a mortar as follows: Patent; Penkler, Lawrence John; US2005/222086; (2005); (A1) English View in Reaxys 6 : EXAMPLE 6 EXAMPLE 6 A pre-mixture of alprazolam (3.87 g) and 2-hydroxypropyl-beta cyclodextrin (150 g) was prepared by geometric dilution in a mortar as follows: Patent; Penkler, Lawrence John; US2005/222086; (2005); (A1) English View in Reaxys

N HO

Rx-ID: 21354677 View in Reaxys 7/25 Yield

Conditions & References Reaction Steps: 2

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1: 74 percent / triphenylphosphine, diethyl azodicarboxylate / tetrahydrofuran / 23 h / Ambient temperature 2: 59 percent / hydrazin hydrate / ethanol / 1) room temp., 2.5 h ; 2) 63 deg C, 3 h . With hydrazine hydrate, triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, ethanol Hester Jr.; Journal of Heterocyclic Chemistry; vol. 17; nb. 3; (1980); p. 575 - 581 View in Reaxys O

H N

P Cl

H N

NH 2

N N

Rx-ID: 25041345 View in Reaxys 8/25 Yield

Conditions & References 7.b : (b) (b) From 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one To a solution of 1.08 g. (4 mmoles) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 20 ml. of dry tetrahydrofuran at room temperature was added 230 mg. of a 50percent dispersion of sodium hydride in oil (4.8 mmoles of hydride). The mixture was warmed gently on the steam bath approximately 1 hour until hydrogen evolution stopped. Dimorpholinophosphinic chloride (1.53 g., 6 mmoles) was added and the resulting mixture was stirred at room temperature for 2 hours. To this mixture was then added to a solution of 593 mg. (8 mmoles) of acethydrazide in 5 ml. of butanol and stirring was continued at room temperature for 10 minutes. Solvents were evaporated and the residue was dissolved in 10 ml. of butanol and heated to reflux for 1 hour. Butanol was evaporated and the residue was partitioned between methylene chloride and water. The methylene chloride layer was dried and evaporated. The residue was crystallized from methylene chloride-ether to give a final productproduct having a m.p. of 223°-225°. in tetrahydrofuran, butan-1-ol Patent; Hoffmann-La Roche Inc.; US4739049; (1988); (A1) English View in Reaxys

O HN

N N

Rx-ID: 25277673 View in Reaxys 9/25 Yield

Conditions & References B : B. B. 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine A sample of 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine was heated under nitrogen at 250° C. for a few minutes. Crystallization of the cooled melt from ethyl acetate gave 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[ 4,3-a]-[1,4]benzodiazepine of melting point 228°-228.5° C. The ultraviolet spectrum (ethanol) had end absorption λ max. 222 (ε= 40,250) and inflections 245 (ε= 15,350), 265 (ε = 6,250) and 290 mμ(ε = 2,850). Anal. Calcd. for C17 H13 CIN4: C, 66.13; H, 4.24; Cl, 11.48; N, 18.15. Found: C, 66.05; H, 4.13; Cl, 11.34; N, 18.00.

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in ethyl acetate Patent; The Upjohn Company; US3987052; (1976); (A1) English View in Reaxys 26 : EXAMPLE 26 EXAMPLE 26 3.3 Parts of 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared in Example 25, is heated at 215° C for 10 minutes under mildly reduced pressure. The fused substance is recrystallized from ethyl acetate to yield 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as colorless needles melting at 225° C to 226° C. Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys 27 : EXAMPLE 27 EXAMPLE 27 A suspension of 3.3 parts of 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared in Example 25 in 20 parts by volume of pyridine is refluxed, whereby the crystals are gradually dissolved. After 2 hours the solvent is evaporated under reduced pressure. The residue is recrystallized from a mixture of acetone and n-hexane to yield 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as colorless needles melting at 224° C to 225° C. in pyridine Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys

O HO

H 2O

N N

O S O

Rx-ID: 25278221 View in Reaxys 10/25 Yield

Conditions & References 24 : 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine EXAMPLE 24 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine 5-Chloro-2-[3-[(methylsulfonyloxy)methyl]-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (5 g.) (see Example 1), dissolved in water-free tetrahydrofuran, was treated with 4 g. of hexamethylenetetramine 1 g. of potassium iodide and 20 ml. of ethanol. The mixture was refluxed for 15 hours, then cooled, filtered, and the filtrate evaporated to dryness to give a yellow gum. The gum was dissolved in chloroform, the chloroform solution extracted with water then chromatographed over 300 g. of Silica Gel and 3percent methanol-97percent chloroform. Fractions 52-132 gave a colorless oil which upon recrystallization from ethylacetate gave 800 mg. of 8-chloro-1methyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine. With 1,3,5,7-tetra-azatricyclo[5.1.1.13,5]decane in ethanol, chloroform Patent; The Upjohn Company; US3993660; (1976); (A1) English View in Reaxys

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H 2N

H N

NH 2

NH N

Rx-ID: 25331249 View in Reaxys 11/25 Yield

Conditions & References 22 : EXAMPLE 22 EXAMPLE 22 A mixture of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.8 parts of acetamidine hydrochloride and 2.5 parts of 2-methylimidazole is fused under heating at 160° C for 10 minutes. Water is added to the mixture, followed by extraction with methylene chloride. The methylene chloride layer is washed with water and dried over sodium sulfate. The solvent is evaporated, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine is yielded. Recrystallization from ethyl acetate yields colorless needles melting at 223° C to 225° C. in water Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys 60 : EXAMPLE 60 EXAMPLE 60 A mixture of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 4N-oxide, 4 parts of acetamidine hydrochloride and 5 parts of 2-methylimidazole is fused under heating at 175° C for 10 minutes. After cooling, water is added to the mixture, followed by extraction with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. Evaporation of the solvent, followed by addition of methanol to the residue yields 8-chloro-1-methyl-6-phenyl-4H-striazolo [4,3-a][1,4] benzodiazepine 5N-oxide as crystals. Recrystallization from methanol yields colorless needles melting at 268° C to 270° C. (decomposition). in methanol, water Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys

H 2N

OH Na +

NH N

O–

N N

Rx-ID: 25331566 View in Reaxys 12/25 Yield

Conditions & References 21 : EXAMPLE 21 EXAMPLE 21 To a solution of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 60 parts by volume of chloroform is added 2.46 parts of ethyl acetoimidate hydrochloride. The mixture is stirred for 8 hours, and then aqueous sodium bicarbonate is added so as to neutralize the mixture. The chloroform layer is separated, washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from ethyl acetate to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as colorless needles. Melting point: 225° C to 226° C. in chloroform Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys

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N I

Rx-ID: 25341628 View in Reaxys 13/25 Yield

Conditions & References

85%

10 : EXAMPLE 10 EXAMPLE 10 A mixture of 0.7 part of hydroxylamine hydrochloride, 4 volume parts of water, 0.6 part of sodium carbonate, 10 volume parts of ethanol and 0.44 part of 5-chloro-2-(3-iodomethyl-5-methyl-s-triazol-4-yl) benzophenone is heated at 70° to 80° C for about 1.5 hour under stirring. Water is added to the mixture, and the whole mixture is extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate, followed by distilling off the solvent. The residue is dissolved in 10 volume parts of ethanol, and 0.2 volume parts of concentrated hydrochloric acid is added thereto. The whole mixture is heated at 70° C for 5 minutes, and the solvent is removed off under reduced pressure. The residue is neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate, followed by subjecting to distillation to remove the solvent. The residue is treated with ethyl acetate, whereby crystals of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo(4,3-a)(1,4) benzodiazepine 5N-oxide are obtained. Recrystallization of the crystals from methanol gives colorless needles melting at 272° to 274° C (decomposition). Yield: 85percent. With hydrogenchloride, sodium hydrogencarbonate in ethanol, water, ethyl acetate Patent; Takeda Chemical Industries, Ltd.; US4082764; (1978); (A1) English View in Reaxys

N HN

Rx-ID: 25341629 View in Reaxys 14/25 Yield

Conditions & References 7 : EXAMPLE 7 EXAMPLE 7 A mixture of 0.7 part of hydroxylamine hydrochloride, 4 volume parts water, 0.64 part of sodium carbonate, 10 volume parts of ethanol and 0.44 part of 5-chloro-2-(3-iodomethyl-5-methyl-s-triazol-4-yl) benzophenone is heated at 70° to 75° C for about one hour under stirring. Water is added to the mixture, and the whole mixture is extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate, followed by distilling off the solvent. The residue is a mixture of 5-chloro-2-(3-hydroxyaminomethyl-5-methyl-s-triazol-4-yl) benzophenone and ring-closure product, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo(4,3-a)(1,4) benzodiazepine 5N-oxide. Former compound is isolated as colorless crystals by treating the residue with ethyl acetate. Recrystallization from ethyl acetate gives colorless needles melting at 154° to 156° C. Isolation yield: 45percent. in water Patent; Takeda Chemical Industries, Ltd.; US4082764; (1978); (A1) English

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View in Reaxys

H 2N

NH N

N N

Rx-ID: 25342337 View in Reaxys 15/25 Yield

Conditions & References 58 : EXAMPLE 58 EXAMPLE 58 To a suspension of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 4N-oxide, prepared in Example 54, and 8 parts of ethyl orthoacetate in 100 parts by volume of ethanol, is added dropwise 1.1 parts by volume of concentrated sulfuric acid. The whole mixture is stirred for about 15 minutes at room temperature, followed by evaporation of the solvent. The residue is neutralized with saturated aqueous sodium bicarbonate, whereby 8-chloro-1-methyl-6-phenyl-4H-striazolo [4,3-a][1,4] benzodiazepine 5N-oxide is obtained as crystals. Recrystallization from a mixture of methanol and dimethyl ether yields colorless needles melting at 272° C to 273° C (decomposition). Elementary analysis C17 H13 ClN4 O: Calculated: C 62.87, H 4.03, N 17.25 Found: C 63.04, H 4.04, N 17.26. With sulfuric acid in ethanol Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys H 2N

N N

Rx-ID: 25342338 View in Reaxys 16/25 Yield

Conditions & References 18 : EXAMPLE 18 EXAMPLE 18 To a suspension of 1.35 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 25 parts by volume of methanol are added 0.6 part of 2-methylimidazole hydrochloride and 6 parts by volume of 1 mole methanol solution of hydrazine hydrate. The mixture is stirred at room temperature for 1.5 hours, followed by addition of 4.8 parts of ethyl orthoacetate and 10 parts by volume of ethanol containing 10percent hydrogen chloride. The mixture is refluxed for 30 minutes, followed by evaporation of the solvent. The residue is neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over sodium sulfate, followed by evaporation of the solvent. The residue is purified by means of silica gel column-chromatography to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine. Recrystallization from a mixture of acetone and n-hexane affords colorless needles. Melting point: 225° C to 226° C. Elementary analysis C17 H13 ClN4: Calculated: C 66.13, H 4.24, N 18.15 Found: C 66.39, H 4.08, N 18.07. With hydrogenchloride, hydrazine hydrate in methanol, ethanol Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys

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H 2N

NH N

Cl N

N N

Rx-ID: 25344541 View in Reaxys 17/25 Yield

Conditions & References 20 : Example 20 Example 20 To a suspension of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 50 parts by volume of acetic anhydride is added 1 part by volume of concentrated sulfuric acid. The resulting solution is left standing at room temperature for 1 hour, poured in ice-water, neutralized with sodium bicarbonate and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from a mixture of acetone and n-hexane to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a]][1,4] benzodiazepine as colorless needles. Melting point: 224° C to 225° C. in (2S)-N-methyl-1-phenylpropan-2-amine hydrate, acetic anhydride Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys

Cl N H 2N

HN ZN

Rx-ID: 25348475 View in Reaxys 18/25 Yield

Conditions & References 24 : EXAMPLE 24 EXAMPLE 24 3.5 Parts of 2-(α-aminoethylidene) hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared in Example 23 is heated on an oil bath at 200° C for 10 minutes, whereby it melts with foaming and then is solidified. Recrystallization from ethyl acetate yields 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as colorless needles melting at 225.5° C to 226.5° C. Patent; Takeda Chemical Industries, Ltd.; US4116956; (1978); (A1) English View in Reaxys

Cl N O

HN NH

N N

Rx-ID: 28278256 View in Reaxys 19/25 Yield 80 %

Conditions & References 2 :EXAMPLE 2 Preparation of alprazolam 2-(2-acetyl hydrazino)-7-chloro-5-phenyl-2H-1,4 benzodiazepine (117.5 g; 0.36 mole) and toluene (11.75 mole.) were added to a RB flask. 0.94 mole of toluene was distilled out at 110-112° C. The reaction mixture was cooled to 90-95° C. and charged with p-toluene sulphonic acid (0.0012 mole). The reaction mixture was then refluxed at 105-110° C. for 10-12 hrs with a Dean-Stark apparatus for water removal. At the end of the reaction (as indicated by TLC), reaction mixture was cooled to 25-30° C.

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The reaction mass was then further cooled to 10-15° C. and stirred at same temperature for 4-5 hrs. The solids precipitated were filtered and washed with cold toluene to obtain crude 8-chloro-1-methyl-6-phenyl-4H-strizolo[4 3-I][1,4] benzodiazepine (alprazolam). The crude alprazolam was purified from isopropanol to obtain 80percent yield of pure alprazolam. With toluene-4-sulfonic acid in toluene, Time= 10 - 12h, T= 90 - 110 °C Patent; Centaur Chemicals Pvt Ltd; US2009/93629; (2009); (A1) English View in Reaxys 80 %

2 : EXAMPLE 2 - Preparation of alprazolam 2-(2-acetyl hydrazino)-7-chloro-5-phenyl-2H-1,4 benzodiazepine (117.5 g; 0.36 mole) and toluene (11.75 mole.) were added to a RB flask. 0.94 mole of toluene was distilled out at 110-112° C. The reaction mixture was cooled to 90-95° C. and charged with p-toluene sulphonic acid (0.0012 mole). The reaction mixture was then refluxed at 105-110° C. for 10-12 hrs with a Dean-Stark apparatus for water removal. At the end of the reaction (as indicated by TLC), reaction mixture was cooled to 25-30° C. The reaction mass was then further cooled to 10-15° C. and stirred at same temperature for 4-5 hrs. The solids precipitated were filtered and washed with cold toluene to obtain crude 8-chloro-1-methyl-6-phenyl-4H-strizolo[4 3-I][1,4] benzodiazepine (alprazolam). The crude alprazolam was purified from isopropanol to obtain 80percent yield of pure alprazolam. With toluene-4-sulfonic acid in toluene, T= 90 - 112 °C Patent; Centaur Chemicals Pvt. Ltd.; EP2250178; (2012); (B1) English View in Reaxys

O O

N N

Rx-ID: 43958472 View in Reaxys 20/25 Yield

Conditions & References

75 %

Synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (alprazolam) (3) A solutionof 1 mmol (0.31 g) of 1-acetyl-7-chloro-5-phenyl-1Hbenzo[e][1,4]diazepin-2(3H)-one (2), N2H5OH (4 mmol,0.2 mL) and NaOAc (4 mmol, 0.2 mL) in 25 ml of AcOHwas refluxed for 12 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, thesolution was cooled and the product was filtered, washedwith water, dried, and crystallized from EtOH. (75 percentyield); m.p = 228–230° C [226–234° C (Jackson andHester, 1980)]; IR (KBr, cm-1): 701, 1643, 1661, 1697,2896, 2922; 1H NMR(CDCl3, 400 MHz): δ 2.4 (s, 3H),7.46 (d, 1H, J = 2.8), 7.3 (m, 3H), 7.54 (d, 2H, J = 10.8),7.68 (m,3H), 7.77 (m, 2H); 13C NMR (CDCl3, 100 MHz):δ 22.3, 117.6, 122.1, 124.3, 126.3, 128.2, 129.4, 131.5,133.7, 134.3, 136.5, 139.2, 156.9, 166.8. With sodium acetate, hydrazine in acetic acid, Time= 12h, Reflux Massah, Ahmad R.; Gharaghani, Sajjad; Lordejani, Hamid Ardeshiri; Asakere, Nahad; Medicinal Chemistry Research; vol. 25; nb. 8; (2016); p. 1538 - 1550 View in Reaxys

NH 2

Rx-ID: 43958474 View in Reaxys 21/25 Yield

Conditions & References Reaction Steps: 3 1: potassium carbonate; ammonium acetate / neat (no solvent) / 3 h / 20 °C

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2: potassium carbonate; potassium hydoxide / neat (no solvent) / 3 h / 20 °C 3: hydrazine; sodium acetate / acetic acid / 12 h / |Reflux With ammonium acetate, sodium acetate, potassium carbonate, potassium hydoxide, hydrazine in acetic acid Massah, Ahmad R.; Gharaghani, Sajjad; Lordejani, Hamid Ardeshiri; Asakere, Nahad; Medicinal Chemistry Research; vol. 25; nb. 8; (2016); p. 1538 - 1550 View in Reaxys

13C

N E

H N

13C

Rx-ID: 2609478 View in Reaxys 22/25 Yield

Conditions & References Time= 0.25h, p= 2Torr , T>200 deg C, Yield given Banks; Digenis; Tetrahedron Letters; vol. 30; nb. 47; (1989); p. 6473 - 6476 View in Reaxys

H 2N

N E

H N

13C

Rx-ID: 21418015 View in Reaxys 23/25 Yield

Conditions & References Reaction Steps: 2 1: NNN-diisopropylethylamine / 0 °C 2: 0.25 h / 2 Torr / T>200 deg C With N-ethyl-N,N-diisopropylamine Banks; Digenis; Tetrahedron Letters; vol. 30; nb. 47; (1989); p. 6473 - 6476 View in Reaxys Cl

14C

N N

Rx-ID: 6365643 View in Reaxys 24/25 Yield

Conditions & References aus 1-<14C>-Essigsaeurehydrazid IIIa Hsi; Journal of Labelled Compounds; vol. 9; nb. 3; (1973); p. 435 - 442 View in Reaxys

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N F

N N

N H

Rx-ID: 24091539 View in Reaxys 25/25 Yield 29%

Conditions & References 44 : [(4-Fluorophenyl)-amino]-N-{2-[4-oxo-4-piperidyl-2-(3-pyridylcarbonyl)butylthio]ethyl}carboxamide Example 44 [(4-Fluorophenyl)-amino]-N-{2-[4-oxo-4-piperidyl-2-(3-pyridylcarbonyl)butylthio]ethyl}carboxamide The title compound was prepared from ethyl 3-[({2-{[(4-fluorophenyl)amino]carbonylamino}ethylthio)methyl]-4-oxo-4(3-pyridyl)butanoate and piperidine as described in the above Example 43 in 29percent yield; ESMS (M+1+) 472. Patent; Nippon Kayaku Co., Ltd.; US6399606; (2002); (B1) English View in Reaxys

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