Finasteride

Finasteride (Rasmusson et al. 1986), a benign prostatic hypertrophy agent, also exists in two polymorphic modifications, designated Forms I and n of finasteride. Chemical consistency was 

The DSC cui-ve for Form I of finasteride is characteristic of an enantiotropic form. Form I is more stable at lower temperatures, with conversion to the higher-temperature stable Form n at the transition point. Cooling samples back through the transition point (unmelted) to room temperature and below results in Form II only. Cooling of melted samples, whether starting with Form I or 11, results in the crystallization of Form II, with no conversion to Form I upon cooling to room temperature and 

Form I of finasteride can be produced by the addition of water to an acetic acid solution of finasteride such that the final weight % of water is equal to or exceeds 84%. If the weight % of water is less than 83%, acetic acid solvates (mono- and di-) of finasteride are obtained that convert to Form II of 

The single-crystal structures of both Forms I and II are known (Wenslow et al. 2000), but no complete single-crystal data exist for the solvates. Minimized force field calculations based upon the crystal structures indicate a lower total energy for Form I than for Form II of finasteride, which is consistent with the thermodynamic conclusions from melting and solubility data. 

Sample preparation 150 u,L Plasma + 150 jjlL ethylene glycol water 40 60, mix, filter (5 H,m), filter (0.22 xm) while centrifuging at 4° at 1000 g for 5 min, iiyect a 150 jtL aliquot of the filtrate onto column A and elute to waste with mobile phase A, after 5 min elute column A to waste with mobile phase B, after 8 min direct the effluent from column A onto column B, after 1.5 min remove column A from the circuit, elute column B with mobile phase D, monitor the effluent from column B. deem column A by eluting to waste with mobile phase C for 19.5 min, re-equilibrate column A with mobile phase A for 4 min. 

Mobile phase A MeCN water 10 90 B MeCN water 25 75 C MeCN water 70 30 D MeCN water 45 55 (Pass mobile phase A and mobile phase B through 35 X 4.6 5 pm Capcell Pak C18 SG-120 (Shiseido) columns before use. Clean these columns with mobile phase C each day.) 

Takano, T. Hata, S. High-performance liquid chromatographic determination of finasteride in human plasma using direct injection with column switching. J.Chromatogr.B, 1996, 676, 141-146 

Sample preparation Condition a 1 mL Baker nitrile SPE cartridge with 1 mL MeOH emd 1 mL water. 1 mL Plasma -i- 50 pL 2 pg/mL IS, vortex for 10 s, add to the SPE cartridge, wash with 2 mL acetone water 10 90, wash with 2 mL water, elute with 250 pL MeOH, add 10 pL water to the eluate, ipject a 200 pL aliquot. 

Mobile phase MeOH MeCN water 6 5 7 Flow rate 1 Injection volume 200 Detector UV 210 

Molecular formula Cz3H36N202 Molecular weight 372.6 CAS Registry Na 98319-26-7 

---

Finaplix Finaprene Finasteride [98319-26-7] Finazoline Fine arts Fine chemicals Fine-coarse difference Fine-grain sugar... 

Adverse reactions with finasteride usually are mild and do not require discontinuing use of the drug. Adverse reactions, when they occur, are related to the sexual drive and include impotence, decreased libido, and a decreased volume of ejaculate... 

C20H2SO3 302-97-6) see Finasteride 3-oxo-4-aza-5a-androstane-17p-carboxylic acid (C ijH2i)N03 103335-55-3) see Finasteride 3-oxo-l,2-benzisothiazole-2(3/7)"ac t c acid ethyl ester 1,1-dioxide... 

Impinging jets, which consist of a cylindrical chamber with two spray nozzles that enter from opposite sides of the chamber, provide small particles with narrow size distribution. The solution oi the material is fed through one nozzle and the crystallization agent through the second nozzle. Finasteride has been cry.stallized in this way a solution of the material in acetic acid plus some water was fed from one nozzle and water from the other the average crystal size was 10 to 15 pm. 

The testes and adrenal glands produce 90% and 10%, respectively, of circulating testosterone. Testosterone enters prostate cells, where predominantly type II 5a-reductase activates testosterone to dihydrotestosterone, which combines with a cytoplasmic receptor. The complex enters the nucleus and induces changes in protein synthesis which promote glandular tissue growth of the prostate. Thus, 5a-reductase inhibitors (e.g., finasteride and dutas-teride) directly interfere with one of the major etiologic factors of BPH. 

AA is started on finasteride 5 mg orally once a day. Four weeks later the patient returns for a follow-up visit and complains that he is not experiencing any symptom improvement. 

McConnell JD, Roehrborn CG, Bautista OM et al. The long term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl 1 Med 2003 349 2387-2398. 

Compare placebo versus finasteride for the prevention of prostate cancer. 

Therefore, the use of finasteride to prevent prostate cancer is currently under debate.7 Because of its established benefit in treating BPH, the 20% to 30% of men over age 50 with BPH may derive the additional benefit of prostate cancer prevention and should be offered treatment with finasteride. In the 70% to 80% of men without BPH, the benefits, side effects (primarily impotence), and risks of finasteride should be discussed prior to initiating therapy. 

Among the candidates considered for development in this series was the t-Bu amide which was subsequently given the name finasteride and became the active ingredient in both PROSCAR and PROPECiA (Figure 3.2). Section 3.1 will tell the story of the development of a manufacturing process for finasteride. As in most programs at Merck, dmg candidates showing potential for improved performance over the lead compound were approved for development as the lead... 

Early process development and modification of the Medicinal Chemistry synthesis for the first kilogram-scale delivery of finasteride... 

When second generation candidates differing from finasteride only at the C17 position were considered for development, a second team was tasked with defining the synthesis while the first delivery of finasteride was being completed. Three ketones were considered as potential back-up compounds, the s-Bu, i-Pr, and i-Bu ketones (2,19, 3 in Scheme 3.4). Ideally, the new route would allow divergence at a late stage of the synthesis to make both finasteride and the ketone selected for... 

To complete the synthesis of finasteride, carboxylic acid 17 in lOml(gTHF)"1 was activated with CDI (1.02equiv) to form the acyl imidazolide 18 (Scheme 3.11). Without isolation, the acyl imidazolide was reacted with 4.6equiv of t-BuNHMgBr heating to reflux in THF for 18h to give finasteride in 98% yield [9]. 

---