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.

tags-synthesis of drugs,method of preparation of Bromazepam,molecular weight Bromazepam, molecular formula of  Bromazepam,structure of Bromazepam,A1%1 cm Bromazepam

Laboratory Synthesis Of Benzatropine

Chemical Synthesis Of Benzatropine

Benzatropine Use: parasympatholytic, antiparkinsonian

Benzatropine MW: 307.44

MF: C21H25NO
LD50: 25 mg/kg (M, i.v.)
CN: endo- 3- (di phenyl methoxy)- 8- methyl- 8- aza bi cyclo [3 .2 .1 ]octane 

Benzatropine mesylate
RN: 132-17-2 EINECS: 205-048-8
MW: 403.54 

MF: C21H25NO · CH4O3S
LD50: 24 mg/kg (M, i.v.); 91 mg/kg (M, p.o.);940 mg/kg (R, p.o.)

Reference(s):
US 2 595 405 (Merck & Co.; 1952; prior. 1949).

Benzatropine solubility :Soluble in chloroform.

Benzatropine Mesilate

Synonyms. Benzatropine Methanesulfonate; Tropine Diphenylmethyl Ether.

Proprietary names. Bensylate; Cogentin.

C₂₁H₂₅NO,CH₄O₃S=403.5

CAS—132–17–2

A white, slightly hygroscopic, crystalline powder. M.p. 141° to 145°.
Soluble 1 in 0.7 of water, 1 in 1.5 of ethanol, and 1 in 2 of chloroform; practically insoluble in ether.

Dissociation Constant.

Benzatropine pK_a10.0 (20°).

Partition Coefficient.

Benzatropine Log P(heptane), 0.4.

Colour Tests.

Mandelin's Test—yellow; Marquis Test—yellow.

Benzatropine Thin–layer Chromatography.

System TA—Rf 13; system TB—Rf 26; system TC—Rf 06; system TL—Rf 02; system TAE—Rf 06. (Acidified iodoplatinate solution, positive.)

Benzatropine Gas Chromatography.

System GA—RI 2302; system GB—RI 2423.

Benzatropine High Performance Liquid Chromatography.

System HA—k 3.7 (tailing peak).

Benzatropine Ultraviolet Spectrum.

Aqueous acid—253, 259 nm (A¹₁=14.5a).

Benzatropine Infra–red Spectrum.

Principal peaks at wavenumbers 1054, 700, 742, 1191, 1204, 1075 cm⁻¹ (KBr disk).

Benzatropine Mass Spectrum.

Principal ions at m/z 83, 140, 82, 124, 96, 97, 42, 125.

Benzatropine Quantification

High performance liquid chromatography.

In plasma—K. Selinger et al.,J. Chromatogr.,1989, 49111, 248–252.

Disposition in the Body.

Absorbed after oral administration.

Benzatropine Toxicity

In a fatality attributed to the ingestion of an unknown quantity of benzatropine tablets, the following postmortem concentrations were reported: blood 0.7 mg/L, liver 1.6 μg/g, urine 0.8 mg/L. In a second case a liver concentration of 2.3 μg/g was found. [G. del Villar and M. Liddy,Bull. Int. Assoc. Forensic Toxicol.,1976, 122, 11–12.]
A 41–year–old male with a history of schizophrenia and drug abuse was found dead. Benzatropine was found at a concentration of 0.183 mg/L in his blood and 7.12 mg/L in his urine. [T. G. Rosano et al.,J. Anal. Toxicol.,1994, 186, 348–353.]

Benzatropine Dose.

0.5 to 6 mg of benzatropine mesilate daily.

Reference

Clarke's Analysis of Drugs and Poisons

Laboratory Synthesis Of Diclofenac

Chemical Synthesis Of Diclofenac

LINK TO THE PATENT DESCRIBING SYNTHESIS OF DICLOFENAC CLICK HERE
RN: 15307-86-5 EINECS: 239-348-5

Diclofenac MW: 296.15

Diclofenac MF: C14H11Cl2NO2

Diclofenac LD50: 170 mg/kg (M, p.o.);62.5 mg/kg (R, p.o.)

CN: 2- [(2 ,6- di chloro phenyl )amino ]benzene acetic acid

monosodium salt

RN: 15307-79-6 EINECS: 239-346-4

Diclofenac MW: 318.14

Diclofenac MF: C14H10Cl2NNaO2

Diclofenac LD50: 116 mg/kg (M, i.v.); 390 mg/kg (M, p.o.);117 mg/kg (R, i.v.); 150 mg/kg (R, p.o.);

Reference(s):

US 3 558 690 (Geigy; 26.1.1971; CH-prior. 8.4.1965, 25.2.1966, 30.3.1966, 20.12.1967).
DAS 1 543 639 (Ciba-Geigy; appl. 7.4.1966; CH-prior. 8.4.1965).
DAS 1 793 592 (Ciba-Geigy; appl. 7.4.1966; CH-prior. 8.4.1965).
US 3 652 762 (Ciba-Geigy; 28.3.1972; prior. 9.12.1968, 29.9.1969, 14.4.1970).
US 3 778 470 (Geigy; 11.12.1973; appl. 2.10.1970; prior. 4.4.1966).
CH 492 679 (Geigy; appl. 30.3.1966).
alternative synthesis:
DOS 2 613 838 (Ikeda Mohando; appl. 31.3.1976; J-prior. 31.3.1975).

melting point diclofenac  156° to 158°.

Diclofenac Sodium

Synonyms. Diclofenacum Natricum; GP-45840.

Proprietary names. Acoflam; Arthrotec; Cataflam; Dicloflex; Diclomax; Diclotard; Diclovol; Diclozip; Econac; Flamatak; Flamrase; Flexotard; Isclofen; Lofensaid; Motifene; Pennsaid; Rheumatac; Rhumalgan; Slofenac; Solaraze; Volraman; Volsaid; Voltaren(e); Voltarol.

C₁₄H₁₀Cl₂NNaO₂=318.1

CAS—15307–79–6

Crystals. MELTING POINT of diclofenac . 283° to 285°.
Solubility at 25° (mg/mL): deionised water (pH 5.2) >9; methanol >24; acetone 6; acetonitrile <1; cyclohexane <1.

Dissociation Constant.

pK_a4.2.

Partition Coefficient.

Log P(octanol/water), 4.5.

Colour Tests.

Liebermann's Test—red–brown; Mandelin's Test—red–brown; Marquis Test—brown (slow).

Thin–layer Chromatography.

System TA—Rf 90; system TD—Rf 25; system TE—Rf 12; system TF—Rf 27; system TG—Rf 29; system TAD—Rf 47; system TAE—Rf 90; system TAJ—Rf 40; system TAK—Rf 64; system TAL—Rf 84. (Chromic acid solution, red.)

Gas Chromatography.

System GA—diclofenac RI 2271, diclofenac-Me RI 2195, diclofenac-Me₂ RI 2220, M (OH-)-Me₂ RI 2460; system GB—RI 2231; system GD—diclofenac-Me RRT 1.42 (relative to n-C₁₆H₃₄); system GL—diclofenac-Me RI 2200, M (OH-)-Me₂ RI 2460.

High Performance Liquid Chromatography.

System HD—k 11.5; system HV—RRT 0.85 (relative to meclofenamic acid); system HX—RI 616; system HY—RI 592; system HZ—retention time 14.8 min; system HAA—retention time 22.1 min; system HAX—retention time 8.7 min; system HAY—retention time 10.0 min.

Ultraviolet Spectrum.

Aqueous acid—273 nm (A¹₁=309b); aqueous alkali—275 nm (A¹₁=351b). 

Quantification

Gas chromatography.

In plasma: limit of detection 100 μg/L, ECD—M. Ikeda et al.,J. Chromatogr.,1980, 183(9) B Biomed. Appl., 41–47. In urine: diclofenac and hydroxy metabolites, ECD—W. Schneider and P. H. Degen,J. Chromatogr.,1981, 217, 263–271.

Gas chromatography–mass spectrometry.

In plasma: limit of detection 2 μg/L, SIM—M. Del Puppo et al.,Biol. Mass Spectrom.,1991, 20, 426–430. In plasma or urine: limit of detection 100 ng/L—A. Sioufi et al.,J. Chromatogr.,1991, 571, 87–100. In plasma: limit of detection 0.2 μg/L—M. R. Borenstein et al.,J. Chromatogr.,1996, 685 B Biomed. Appl., 59–66. In urine: diclofenac and other NSAIDs—B. M. el Haj et al.,Forensic Sci. Int.,1999, 105, 141–153. In urine: diclofenac and other NSAIDs, limits of detection 10 to 50 μg/L—H. H. Maurer et al.,J. Anal. Toxicol.,2001, 25, 237–244.

High performance liquid chromatography.

In plasma: limit of detection 5 μg/L, UV detection—K. K. H. Chan et al.,Anal. Lett. (Part B),1982, 15, 1649–1663. In plasma: limit of detection 6 μg/L, fluorescence detection—B. Wiese and J. Hermansson,J. Chromatogr.,1991, 567, 175–183. In plasma: limit of quantification 5 μg/L, UV detection—L. A. Brunner and R. C. Luders,J. Chromatogr. Sci.,1991, 29, 287–291. In plasma or cerebrospinal fluid: limit of detection <1 μg/L, electrochemical detection—L. Zecca et al.,J. Chromatogr.,1991, 567, 425–432. In plasma: limit of detection 1 μg/L, UV detection—S. R. Santos et al.,Braz. J. Med. Biol. Res.,1992, 25, 125–128. In serum: limit of quantification 20 μg/L, fluorescence detection—J. Moncrieff,J. Chromatogr.,1992, 577, 185–189. In plasma or synovial fluid: diclofenac and other NSAIDs—I. S. Blagbrough et al.,J. Chromatogr.,1992, 578, 251–257. In plasma: limit of detection <2.5 μg/L, UV detection—R. B. Miller,J. Chromatogr.,1993, 616, 283–290. In plasma or urine: limit of detection 0.2 mg/L, UV detection—A. Avgerinos et al.,J. Chromatogr.,1993, 619, 324–329. In serum: limit of detection 10 μg/L—S. Y. Zhang et al.,Yao Xue Xue Bao,1994, 29, 228–231. In aqueous humour: diclofenac and flurbiprofen, limit of detection for diclofenac 0.3 ng, UV detection—M. Riegel and P. P. Ellis,J. Chromatogr.,1994, 654 B Biomed. Appl., 140–145. In plasma: limit of detection 3 μg/L, UV detection—A. Hanses et al.,Arch. Pharm. (Weinheim),1995, 328, 257–260. In urine: diclofenac and its metabolites, limit of quantification 0.4 mg/L—R. J. Sawchuk et al.,Pharm. Res.,1995, 12, 756–762. In urine: diclofenac and other NSAIDs, limit of detection for diclofenac 0.05 mg/L, UV detection—T. Hirai et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 692, 375–388. In serum or aqueous humour: limit of detection 1 μg/L, UV detection—O. Kuhlmann and G. J. Krauss,J. Pharm. Biomed. Anal.,1997, 16, 553–559. In plasma: diclofenac and flurbiprofen—G. Giagoudakis and S. L. Markantonis,J. Pharm. Biomed. Anal.,1998, 17, 897–901. In aqueous humour: diclofenac and oxybuprocaine, limit of detection for diclofenac 500 ng/L, electrochemical detection—O. Kuhlmann et al.,J. Pharm. Biomed. Anal.,1998, 17, 1351–1356. In urine: diclofenac and other NSAIDs, limit of quantification for diclofenac 0.02 mg/L, UV detection—A. Bakkali et al.,J. Chromatogr. B Biomed. Sci. Appl.,1999, 729, 139–145. In plasma: diclofenac and aceclofenac, limit of detection 10 μg/L—H. S. Lee et al.,J. Pharm. Biomed. Anal.,2000, 23, 775–781. In plasma: limit of detection 5 μg/L—C. Arcelloni et al.,J. Chromatogr. B Biomed. Sci. Appl.,2001, 763, 195–200.

Disposition in the Body.

Well absorbed after oral administration but undergoes significant first–pass metabolism. Up to about 70% of a dose is excreted in the urine in 3 days, including 20 to 40% as glucuronide and sulfate conjugates of the major metabolite 4′-hydroxydiclofenac (active) and up to about 15% as conjugates of unchanged diclofenac. Other metabolites identified in the urine include 5–hydroxydiclofenac (about 12% of the dose), 3′-hydroxydiclofenac, and 4′,5–dihydroxydiclofenac. About 10 to 20% of a dose is excreted in the bile as 4′-hydroxydiclofenac and less than 5% as unchanged drug. Diclofenac enters the synovial fluid and maximum concentrations are measured 2 to 4 h after the peak plasma levels have been reached. Diclofenac is excreted in breast milk but in quantities so small that no adverse effects on breast–fed infants would be expected.

Therapeutic concentration

Following oral administration of 50 mg of diclofenac sodium three times a day to 4 subjects, peak plasma concentrations of 0.1 to 2.2 mg/L (mean 0.8) of diclofenac and 0.3 to 2.0 mg/L (mean 1.2) of 4′-hydroxydiclofenac were reported 3 h after a dose; peak concentrations in synovial fluid of 0.1 to 0.6 mg/L (mean 0.3) of diclofenac and 0.2 to 1.0 mg/L (mean 0.6) of 4′-hydroxydiclofenac were attained in 3 h; concentrations in synovial fluid exceeded those in plasma after 4 h. [P. D. Fowler et al.,Eur. J. Clin. Pharmacol.,1983, 25, 389–394.]
Diclofenac was administered as a single oral 150 mg dose to healthy subjects (n = 6) and to patients with either chronic active hepatitis (n = 6) or alcoholic cirrhosis (n=6). Peak plasma concentrations of diclofenac, 3′-hydroxydiclofenac, 4′-hydroxydiclofenac, and 3′-hydroxy–4′,5–methoxydiclofenac of 5.699, 0.412, 2.613, and 0.385 mg/L were attained at 0.63, 0.79, 0.88, and 5.8 h, respectively, in healthy subjects. The equivalent respective values in patients with hepatitis were: 6.574, 0.392, 2.786, and 0.306 mg/L at 0.42, 0.58, 0.50, and 4.0 h and in patients with cirrhosis were: 11.59, 0.264, 2.481, and 0.191 mg/L at 0.33, 1.04, 0.75, and 7.0 h. [J. S. Lill et al.,J. Clin. Pharmacol.,2000, 40, 250–257.]
In 20 healthy subjects given a single oral dose of diclofenac 100 mg as 2 different sustained–release tablets, respective peak plasma concentrations of 1.161 and 0.799 mg/L were attained in 4.2 and 4.5 h. [S. Zmeili et al.,Int. J. Clin. Pharmacol. Ther.,1996, 34, 564–570.]

Toxicity

A 19–year–old man was admitted to hospital following the ingestion of 1.5 g of diclofenac sodium and 4 g of chlormezanone. Plasma diclofenac concentrations of 60.1 mg/L and 0.19 mg/L were reported at 7 and 15 h, respectively; chlormezanone could not be determined. The subject recovered after about 2 days. [P. Netter et al.,Eur. J. Clin. Pharmacol.,1984, 26, 535–536.]

Bioavailability.

About 50 to 60%

Half–life.

Plasma half–life, about 1 to 2 h; synovial fluid half–life 3 to 6 h.

Volume of distribution.

0.17 L/kg.

Clearance.

Plasma clearance, about 4 mL/min/kg.

Protein binding.

In plasma, more than 99%.

Note.

For reviews of diclofenac see R. W. Brogden et al.,Drugs,1980, 20, 24–48 and N. M. Davies and K. E. Anderson,Clin. Pharmacokinet.,1997, 33, 184–213.

Dose.

75 to 150 mg of diclofenac sodium daily in divided doses.

Reference

Clarke's Analysis of Drugs and Poisons

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Laboratory Synthesis Of Benazepril

Preparation of  Benazepril

IUPAC name Benazepril  [S- (R *,R *)]-3- [[1- (ethoxy carbonyl)- 3- phenyl propyl ]amino]- 2 ,3 ,4 ,5- tetra hydro- 2- oxo- 1 H- 1- benzazepine- 1- acetic acid

Benazepril Use: antihypertensive (ACE inhibitor)

Benazepril MW: 424.50

Benazepril MF: C24H28N2O5

Benazepril M.p. 148.5°.

Proprietary names. Briem; Cibace; Cibacen; Cibacene; Labopal; Lotensin; Tensanil; Zinandril.

C₂₄H₂₈N₂O₅,HCl=461.0

CAS—86541–74–4

A white to off–white crystalline powder. It is soluble in water, ethanol and methanol.

Partition Coefficient.

Log P(octanol/water), 3.50.

Gas Chromatography.

System GP—RI 3030 (benazepril-ME); RI 2985 (M (benazeprilate)-ME3).

Column: 3% OV-101 on Gaschrom Q, 80–100 mesh (Ciba-Geigy), pyrex glass (1.5 m × 2 mm i.d.). Column and injector port temperature: 275°. Carrier gas: helium, flow rate 30 mL/min. MS detection (EI, SIM). Retention times: benazepril (methyl ester derivative) 2.55 min; benazeprilat (derivative) 2.3 min. [G. Kaiser et al.,J. Chromatogr.,1987, 419, 123–133].

High Performance Liquid Chromatography.

System HAA—retention time 17.0 min.

Column: C₁₈ (RP-BDS, 5 μm packing, 250 × 3 mm i.d.). Mobile phase: sodium dihydrogen phosphate (0.025 M, pH 4.8):acetonitrile (55:45). 0.4 mL/min flow rate. UV detection (λ=250 nm). Retention time: benazepril hydrochloride, 4.95 min. [I. E. Panderi and M. Parissi-Polou,J. Pharm. Biomed. Anal.,1999, 21, 1017–1024].

Column: Hypersil ODS (5 μm, 250 × 4.5 mm). Mobile phase: sodium heptanesulfonate (20 mM, pH 2.5):acetonitrile (5% THF) (52:48 v/v), 1.0 mL/min flow rate. UV detection (λ=215 nm). Retention time: 15 min. [D. Bonazzi et al.,J. Pharm. Biomed. Anal.,1997, 16, 431–438].

Ultraviolet Spectrum.

Aqueous acid (0.2 M NH₂SO₄)—237 nm; basic—241 nm; aqueous acid (0.1 M hydrochloric acid)—237.2 nm (hydrochloride salt).

Reference(s):
Clarke's Analysis of Drugs and Poisons
Watthey, J.W.H. et al.: J. Med. Chem. (JMCMAR) 28, 1511 (1985).
US 4 410 520 (Ciba-Geigy; 18.10.1983; prior. 11.8.1981, 9.11.1981, 19.7.1982).
EP 72 352 (Ciba-Geigy; appl. 5.8.1982; USA-prior. 11.8.1981, 9.11.1981).

Laboratory Synthesis Of Benserazide

Preparation of Benserazide

IUPAC name Benserazide CN: DL- serine 2- [(2 ,3 ,4- tri hydroxy phenyl )methyl ]hydrazide

Benserazide Use: antiparkinsonian (in combination with levodopa), decarboxylase inhibitor

Benserazide MW: 257.25 

Benserazide MF: C10H15N3O5

Benserazide monohydrochloride

MW: 293.71 MF: C10H15N3O5 · HCl
LD50: 5 g/kg (M, p.o.);5300 mg/kg (R, p.o.)

An off–white crystalline powder. M.p. 146° to 148°.Soluble 1 in 3 of water, 1 in 118 of ethanol, 1 in 66 of acetone, 1 in 180 of chloroform and 1 in 455 of ether.

Colour Tests.

Ammoniacal silver nitrate—black; p-Dimethyl–aminobenzaldehyde—red/-; Ferric chloride—green–brown; Folin–Ciocalteu reagent—blue; Methanolic potassium hydroxide—red; Millon's reagent—red–orange; Nessler's reagent—black; Palladium chloride—orange→brown; Potassium dichromate—brown.

Thin–layer Chromatography.

System TA—Rf 01; system TB—Rf 00; system TC—Rf 01; system TL—Rf 03; system TAE—Rf 7.

High Performance Liquid Chromatography.

System HX—RI 35.

Ultraviolet Spectrum.

Aqueous acid—203, 269 nm.

Reference(s):
Clarke's Analysis of Drugs and Poison
DE 1 165 607 (Roche; appl. 8.5.1962; CH-prior. 16.6.1961).
US 3 178 476 (Roche; 13.4.1965; CH-prior. 16.6.1961).
L-form:
US 3 557 292 (Roche; 19.1.1971; appl. 16.8.1968).
DE 1 941 284 (Roche; appl. 13.8.1969; CH-prior. 16.8.1968).
DAS 1 966 821 (Roche; appl. 13.8.1969; CH-prior. 16.8.1968).

Laboratory Synthesis Of Barbital

BARBITAL SYNTHESIS

IUPAC NAME OF Barbital : 5 ,5- di ethyl- 2 ,4 ,6 (1 H ,3 H ,5 H)- pyrimidine trione

Use: hypnotic

Barbital MW: 184.20

Barbital MF: C8H12N2O3
Barbital LD50: 600 mg/kg (M, p.o.)

A white crystalline powder. A solution in water slowly decomposes. M.p. about 190°.

Soluble 1 in 5 of water (1 in 2.5 of boiling water) and 1 in 400 of ethanol; practically insoluble in chloroform and ether.

Dissociation Constant.

pK_a8.0 (25°).

Partition Coefficient.

Log P(octanol/water), 0.7.

Colour Tests.

Koppanyi–Zwikker Test—violet; Mercurous Nitrate—black.

Thin–layer Chromatography.

System TD—Rf 41; system TE—Rf 32; system TF—Rf 61; system TH—Rf 51; system TAD—Rf 57; system TAE—Rf 84. (Mercuric chloride–diphenylcarbazone reagent, positive; mercurous nitrate spray, black; Zwikker's reagent, pink.)

Gas Chromatography.

System GA—barbital RI 1489, barbital-Me₂ RI 1420, barbital-Me (metharbital) RI 1470, barbituric acid-Me₃ RI 1645; system GF—RI 2230; system GAJ—RRT 0.612 (relative to methylphenobarbital).

High Performance Liquid Chromatography.

System HG—k 1.11; system HH—k 0.63; system HX—RI 308; system HY—RI 258; system HZ—retention time 2.2 min; system HAA—retention time 10.4 min; system HAL—retention time 1.4 min.

Ultraviolet Spectrum.

Borax buffer 0.05 M (pH 9.2)—239 nm (A¹₁=549a); M sodium hydroxide (pH 13)—254 nm (A¹₁=427b).

Reference(s):
Clarke's Analysis of Drugs and Poisons
Fischer; Dilthey: Justus Liebigs Ann. Chem. (JLACBF) 335, 338 (1904).