Laboratory Synthesis Of Bromazepam

Chemical  Synthesis Of Bromazepam

BromazepamUse: tranquilizer

Bromazepam CN: 7- bromo- 1 ,3- di hydro- 5- (2- pyridinyl)- 2 H- 1 ,4- benzo diazepine- 2- one

Bromazepam MW: 316.16 MF: C14H10BrN3O

Bromazepam LD50: 879 mg/kg (M, p.o.);1950 mg/kg (R, p.o.)
Bromazepam Reference(s):a US 3 100 770 (Roche; 13.8.1963; appl. 11.8.1961).

US 3 182 065 (Roche; 4.5.1965; appl. 9.4.1964; prior. 19.4.1963).

US 3 182 066 (Roche; 4.5.1965; appl. 9.4.1964; prior. 19.4.1963).

US 3 182 067 (Roche; 4.5.1965; appl. 9.4.1964).

Fryer, R.I. et al.: J. Pharm. Sci. (JPMSAE) 53, 264 (1964).

modified methods:

DAS 2 233 483 (Roche; appl. 7.7.1972; GB-prior. 8.7.1971, 7.10.1971).

DOS 2 252 378 (Roche; appl. 25.10.1972; CH-prior. 18.11.1971).

alternative synthesis of 2-(2-amino-5-bromobenzoyl)pyridine:

DAS 2 256 614 (Roche; appl. 17.11.1972).

b DAS 1 813 241 (Roche; appl. 6.12.1968; J-prior. 8.12.1967, 9.12.1967, 12.12.1967,

25.4.1968).

combination with sulpiride:

DAS 2 342 214 (Roche; appl. 21.8.1973; CH-prior. 21.9.1972).

A white or yellowish crystalline powder. M.p. 237° to 238.5° with decomposition.
Practically insoluble in water, sparingly soluble in alcohol and in dichloromethane.

Bromazepam Dissociation Constant.

pK_a2.9, 11.0.

Partition Coefficient.

Log P(octanol/water), 2.05.

Colour Test.

Formaldehyde–Sulfuric Acid—yellow.

Bromazepam Thin–layer Chromatography.

System TA—Rf 61; system TB—Rf 6; system TC—Rf 41; system TD—Rf 13; system TE—Rf 63; system TF—Rf 18; system TL—Rf 53; system TAD—Rf 47; system TAE—Rf 73; system TAF—Rf 69; system TAJ—Rf 34; system TAK—Rf 04; system TAL—Rf 63.

Bromazepam Gas Chromatography.

System GA—bromazepam RI 2665, M (3-OH-) RI 2470; system GB—bromazepam RI 2760, bromazepam-TMS RI 2702; M (3-OH-)-TMS₂ RI 2650; system GG—RI 3280.

Column: DB-17 (30 m × 0.32 mm i.d., 0.25 μm film thickness). Column temperature: 150°, held for 1 min, ramp to 230°, held for 5 min, ramp to 300° held for 9 min at 10°/min. Injector and detector temperatures: 270° and 300°, respectively. Carrier gas: helium (pre–column pressure, 80 kPa). Detection: ECD. Retention time: 18.0 min. [F. Guan et al.,J. Anal. Toxicol.,1999, 23, 54–61.]

Column: HP5-MS (5% phenyl:95% siloxane, 30 m × 0.25 mm, 0.25 μm film thickness). Column temperature: 60° held for 1 min, ramp to 295° at 30°/min, held for 6 min. Injector temperature: 250°. Carrier gas: helium, flow rate 1 mL/min. MS detection (NCI mode). Retention time: 9.7 min. [P. Kintz et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 700, 119–129.]

Bromazepam High Performance Liquid Chromatography.

System HI—k 2.32; system HK—k 2.99; system HX—RI 397; system HY—RI 331; system HZ—retention time 3.0 min; system HAA—retention time 14.7 min; system HAF—retention time 6.6 min (tailing peak); system HAX—retention time 5.8 min; system HAY—retention time 5.1 min; system HBH—k 1.63; system HBI—k 0.80; system HAL—retention time 8.1 min; system HAM—not detected.

Column: RP C₁₈ (150 × 3.9 mm i.d., 5 μm). Mobile phase: water:acetonitrile:triethylamine (700:300:4), adjusted to pH 7.4 with phosphoric acid, flow rate 2 mL/min. UV detection (λ = 240 nm). Retention time: bromazepam, 2.1 min, α-hydroxytriazolam (IS), 3.2 min. [Le Solleu et al.,J. Pharm. Biomed. Anal.,1993, 11, 771–775.]

Bromazepam Ultraviolet Spectrum.

Aqueous acid—239, 345 nm; aqueous alkali—237 nm (A¹₁=920b), 348 nm; methanol—233 nm (A¹₁=1050b), 320 nm (A¹₁=61b).

Bromazepam Infra–red Spectrum.

Principal peaks at wavenumbers 1685, 825, 750, 802, 1315, 1230 cm⁻¹.

Bromazepam Mass Spectrum.

Principal ions at m/z 236, 317, 315, 288, 316, 286, 208, 78; 3–hydroxybromazepam 79, 78, 52, 105, 304, 314, 316, 51.

Quantification.

Gas chromatography.

In plasma: limit of detection 5 μg/L, ECD—U. Klotz,J. Chromatogr.,1981, 222(21) B Biomed. Appl., 501–506. In plasma or blood: bromazepam and other benzodiazepines, ECD and NPD—P. Lillsunde and T. Seppala,J. Chromatogr.,1990, 533, 97–110. In hair: limit of detection, 20 pg/mg hair, MS (NCI mode)—P. Kintz et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 700, 119–129. In urine: bromazepam and other benzodiazepines, limit of detection for bromazepam 160 μg/L, ECD—F. Guan et al.,J. Anal. Toxicol.,1999, 23, 54–61.

Bromazepam Gas chromatography–mass spectrometry.

In tissue: limit of quantification, 50 ng/g tissue, SIM—X.X. Zhang et al.,J. Chromatogr.,1996, 677 B Biomed. Appl., 111–116. In urine: bromazepam, diazepam, and nordazepam, TOF–MS, comparison with MS and ECD—B. Aebi et al.,Forensic Sci. Int.,2002, 128, 84–89.

Bromazepam High performance liquid chromatography.

In plasma: limit of detection 5 μg/L, UV detection—H. Hirayama et al.,J. Chromatogr.,1983, 277(28) B Biomed. Appl., 414–418. In plasma: limit of detection 3 μg/L, UV detection—A. Boukhabza et al.,Analyst,1989, 114, 639–641. In plasma: limit of detection, 50 μg/L, UV detection—H. Le Solleu et al.,J. Pharm. Biomed. Anal.,1993, 11, 771–775. In serum: bromazepam and other benzodiazepines, UV detection—E. Tanaka et al.,J. Chromatogr.,1996, 682 B Biomed Appl., 173–178 and E. Tanaka et al.,J. Chromatogr. B Biomed. Sci. Appl.,1998, 709, 324.

Bromazepam Disposition in the Body.

Well absorbed after oral administration and peak plasma concentrations are usually achieved within 2 h. About 70% of a dose is excreted in the urine in 72 h, including about 2% of the dose as unchanged bromazepam, about 27% as the glucuronide of 3–hydroxybromazepam, about 40% as the glucuronide of 2–amino–5–bromo–3–hydroxybenzoylpyridine, and less than 1% as 2-(2–amino–5–bromobenz–oyl)-pyridine.

Bromazepam Therapeutic concentration

After a single oral dose of 12 mg, administered to 10 subjects, peak plasma concentrations of 0.11 to 0.17 mg/L (mean 0.13) were attained in 1 to 4 h. Steady–state concentrations of 0.08 to 0.15 mg/L (mean 0.12) were measured during dosing of 6 subjects with 9 mg daily. [S. A. Kaplan et al.,J. Pharmacokinet. Biopharm.,1976, 4, 1–16.]
Administration of bromazepam as a slow–release formulation to 24 healthy subjects after an overnight fast resulted in peak plasma concentrations of 9.09 to 13.00 μg/L (mean 11.05 μg/L) attained in 4 to 16 h (mean 8 h); the corresponding values for a conventional–release preparation administered as 2 separate 1.5 mg doses, 12 h apart, were 8.91 to 11.50 μg/L (mean 10.21 μg/L) in 2 to 8 h (mean 8 h). [F. E. Lerner et al.,Arzneimittelforschung,2001, 51, 955–958.]

Toxicity

In a 68–year–old woman who was found unconscious and barely breathing, bromazepam intoxication was discovered to be the cause (a serum level of 6 mg/L was detected); normal functions were restored 12 days after the ingestion. [J. Rudolf et al.,Dtsch. Med. Wochenschr.,1998, 123, 832–834.]
A 42–year–old woman ingested 420 mg bromazepam in a suicide attempt and survived despite being found unconscious outdoors in a state of semi–undress and suffering from hypothermia. About 12 h after the ingestion the blood concentration of bromazepam was 7.7 mg/L. [K. Michaud et al.,Forensic Sci. Int.,2001, 124, 112–114.]

Bromazepam Half–life.

Plasma half–life, 8 to 19 h (mean 12).

Bromazepam Volume of distribution.

About 0.9 L/kg.

Bromazepam Protein binding.

In plasma, 70%.

Bromazepam Dose.

Usually 3 to 18 mg daily; up to a maximum of 60 mg daily in divided doses has been given to hospitalised patients.

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