非那甾胺的合成

Transactions of Tianjin UniversityVol. 7 No.4Dec.2001sssss8assss8s8s8 Experimental ResearchSYNTHESIS OF FINASTERIDEL/ Xiao- jun, FANG Fang，WANG Xiao j/, CHEN Li gong(School of Pharmaceutical Science and Technology , Tianjin University ,Tianjin 300072 ,China)Abstract:As a kind of substrate competition-type 5a- reductase inhibitor , finasteride is a promisingmedicine used in the clinical treatment of benign prostatic hyperplasia (BPH). In this paper,a newroute for the synthesis of finasteride from pregnenolone was proposed. Thus，pregnenolone was con-verted to finasteride in 10 steps,i. e.，ammoniumation, methoxylation, Oppenauer oxidation, by-drolyzation,cleavage of O*-double bond by oxidation ,ring closure by ammonia，hydrogenation of△°-double bond ,esterification with methanol ,dehydrogenation of 1,2-position in A- ring and Bodroux re-action. In this route ,expensive reagent 2,2' -dipyridyl-disulfide commonly used in previous literaturewas avoided. All of the desired compounds were characterized by MS or/and NMR. The overall yieldof finasteride was 13. 67% based on pregnenolone.Key words :finasteride ;synthesis ;pregnenoloneFinasteride 1, N-(l-butyl )-3-oxo-4-aza-5a-an- NMR spectroscopies are taken from V arian Unity- Plusdrost- 1-ene-17β-carboxamide is a kind of azasteroidal 400. Mass spectroscopies are taken from HP 5989 GC-compound. It has found use in the treatment of benign MS(EIMS) and APEX I FT-ICRMS.prostatic hyperplasia (BPH)[1~3] that is bothering the 2. 1 Pregnenolone- 21- pyridinium iodide(3)male adults. In addition,finasteride is also used in thelodine(4. 32 g,17. 0 mmol) was added portion-treatment of the loss of hair[4.5] and in the prevention wise over 15 min~ 30 min to an initially warmed (90of prostate cancer recently[6]C) solution of pregnenolone 2(5.0 g,15. 6 mmol) inThe reported synthesis of finasteride from preg- 13. 3 mL of pyridine. The exothermic reaction wasnenolone usually involved more than ten steps, the .warmed to reflux during adding and was stirred for angraphical synthetic routes of finasteride was reviewed additional 1 h while the temperature remained higherin Ref. [7]. .than 100 C. The mixture cooled gradually to roomtemperature was filtered. The solid was washed with1 General Methodpyridine (4 mLX3) and Et2O (5 mLX 3) successive-ly. Air-drying gave 7. 73 g(95. 0% yield) of preg-In this paper a new route is designed for the totalnenolone-21-pyridinium iodide 3 as a yellow-tan pow-synthesis of finasteride from pregnenolone and satis-der,mp 228 C~230 C(in Ref.[1] mp 228 C~ 230factory results are obtained. In brief ,pregnenolone wasC). MS:M+ 521.converted to finasteride in ten steps. However ,the uti-2.2 MethyI 3a-hydroxy- 5- androstene- 17β-carboxylate(4)lization of expensive reagents such as 2, 2'-dipyridyI-After 0. 6 g(26. 1 mmol) of sodium was carefullydisulphide was avoided ,and the overall yield was up todissolved in 80 mL of anhydrous methanol under nitro-13.67% based on pregnenolone. The practical route isgen,the resultinr solutinn nf MeONa in methanol wasillustrated in Scheme 1.中国煤化工heated topyridinium iodide 3(10. 0 g,MYHIC NMH G in portions over 152 Experimental SectionMelting points are measured with Yanaco MicroReceived date : 2001-04- 20;revised date :2001 -09- 07.Melting_ Point Apparatus (thermometer uncorrected).Li Xiaojun . born in 1967 ,male ,lecturer.TRANSACTIONS OF TIANJIN UNIVERS/TY Vol. 7 No.42001min. The heavy slurry gradually dissolved and the dark were washed with 1 : 1 MeOH-water until the colorsolution was refluxed for another hour. Upon cooling was largely extracted. Drying in an air stream offeredto 45 C ina period of 2 h,the ester crystallized. 60mL 5. 71 g(93. 0% yield) of crude ester 4,mp 174 C~175of water was added with vigorous stirring followed by C (in Ref.[1]mp 173 C~176 C). MS:M+ 332.13 Cneutralization with 6 mol/L HCl solution. After keep- NMR (CDClg): 174. 670，141. 019,121. 466,71. 825,ing for 1 h,the solids were removed by filtration and 56. 306,55. 356,19.512 5,13. 431.COCH,COCH.H+C0OCH,Pyridine,1CH,ONaCy clohexamuneAl(/-Pro)/Toluene0H-OH-2)(3COOCH.COOH .COOH. 10%KOH/CH.CH.OHKMnONH，Nalo.oH-0025)(67)C0OCH, .PUB+CH.OH/HC1(PhSeO):OChlorobenzeneo个 NHH{ HHH(10)8)(9COOCH,CONIC(CH.)? EtMg6r/-Butylamineo个N-(1)(11)Scheme 1 Practical route of the total synthesis of finasteride2.3 MethyI 3 -0x0- 4 androstene- 17β -carboxylate(5)2.4 3 -ox0- 4- androstene- 17β- carboxylic acid(6)A solution of the above 3-hydroxy-steroid 4 (5. 01. 0 g(~3. 0 mmol) of the above ester 5 wasg，15.05 mmol) in 72.5 mL of toluene and 13 mL saponified in a refluxing solution of 10% KOH in 6(0.126 mol) of cyclohexanone and 24. 7% Al(i-PrO)。ml of 95% ethanol for 6 h. Dilution with aqueous acid(2. 75 g,3.5 mmol) were refluxed for 1 h. The result- (6 mol/L HCl) and water followed by filtration gaveing mixture was treated with 50 mL of saturated NaClon drying 0. 91 g (95. 8% yield) of 3- oxo-4-an-solution and filtered. The filtrate was dried by anhy- drostene- 17β carboxylic acid 6,mp 245 C~246 C (indrous Na2SO,after removing solution by evaporation，Ref.[1]mp 247 C~249 C).MS: M+ 316，M/(M+the residue was stirred in petroleum ether(60 C~90 1) = 5中国煤化工199. 670，179. 372，C) at 5 C for 15 min,3.71 g (74.5% yield) of white 171. 175,:MHCNMHGpowder 5 was obtained by filtration and drying in vac- 2. 517β- carboxy-5- 0X0-A -nor-3, 5- secoandrostan-3-uum,mp 126 C~127 C(in Ref.[1] mp 128 C~130oic acid(7)C). MS:M+ 330.13C NMR(CDCl3):199. 447,174. 421,To a solution of 3.7 g(~11.6 mmol) of 3- oxo-4-171. 004,124. 053.androstene- 17β-carboxylic acid 6 in 66. 6 mL of t-bu-TRANSACTIONS OF TIANJIN UNIVERSITY Vol. 7No.42001德利康tanol at 80 C was added to a solutionof 3.7 g of sodi-of methyl ester 10 was obtained by filtration , washingum carbonate in 11. 1 mL of water.A warm(65 C) so- and drying,mp 288 C~289 C(in Ref.[2] mp 286 Clution of 17. 8 g of sodium metaperiodate and 0.15gof ~ 289 C). MS:M+ 333. 18C NMR (CDCl3):173. 626，potassium permanganate in 55. 5 mL of water was 173. 542,170. 177,59. 737.added at such a rate that the reaction mixture was 2. 9 MethyI 3- 0x0-4 aza- 5a- androst- 1- ene- 17β-maintained at 80 C. After addition, the mixture wascarboxylate(11)heated at reflux for 1 h. Then the inorganic salts wereA solution of 2.1 g(~6.3 mmol) of methyl 3-removed by filtration. The l-butanol in the filtrate was oxo-4-aza- 5a androstane- 17β- carboxylate 10 and 3.2 gremoved at a reduced pressure and the aqueous residue (~8. 8 mmol) of benzeneseleninic anhydride in 52. 5was acidified with concentrated hydrochloric acid. The mL of chlorobenzene was heated at reflux for 2 h. Theseparated gum was extracted into ethyl acetate anreflux condenser was switched to a distillation headwas washed with saturated sodium chloride solution，and the mixture was distilled slowly to remove solu-then dried and concentrated to an off-white crystal 7 tion(2 h). The residue as a solution in dichlorometh-(2.87 g,73. 2% yield),mp 187 C~188 C(in Ref.[2]ane was washed with saturated NaHCO3 solution andmp 198 C~192 C). MS:M+ 336. 13 C NMR(CDClx): saturated NaCl solution,then this material was chro -213.728,174. 636,174. 582.matographed on silica gel eluting first with dichloro-2.63-0x0-4-aza-5-androstene- 17B-carboxylicmethane and then with 4:1(v/v) dichloromethane-ace-acid(8)tone. The desired product obtained by evaporationA suspension of 2.8 g(~8. 2 mmol) of the dioic amounted to 1.24 g 11 (59.4 % yield),mp 278 C-acid 7 obtained in the above step in 30 mL of cold (~ 280 C(in Refs. [2] and [3] mp 278 C~ 280 C).5 C) ethylene glycol was treated with 1.2 g(70.6 MS: M+ 331.13 C NMR (DM SO):169. 183,161.505，mmol) of ammonia. The resulting solution was heated 145. 867,117. 817,54.453.up to 180 C at a rateof 3 C/min and was held at that 2. 10 N-(t-butyl)-3-0x0-4- aza-5a- androst- 1- ene-temperature for 30 min. After cooling,100 mL of wa-17β- carboxamide( 1 , finasteride )er was added and the mixture was acidified with 6In a flask equipped with an overhead stirrer,a ni-mol/L hydrochloric acid to a pH of 1. 5. The product trogen inlet ,and reflux condenser,84 mL of dry THFwas removed and washed with water, and then air- and 2.8 mL(26. 4 mmol) of t-butylamine were placed.dried to leave 2.2 g 8 (84. 6% yield),mp 305 C~306 The solution was cooled to 10 C and 12. 2 mL of 2C(in Ref. [2] mp 310 C). MS:M+ 317.13 C NMR mol/L ethyl magnesium bromide in THF was added(CDCl;):174. 743,167. 814,140. 759,101. 024.maintaining the reaction temperature below 30 C .2.73- 0x0-4- aza- 5a- androstane- 17β- carboxylicThen 2 g(~ 6.0 mmol) of the above unsaturatedacid(9)methyl ester 11 was added. After refluxing for 5 h,theA solution of 1.0 g(~3. 15 mmol) of the above mixture was added to 50 mL cold(10 C) solution ofO'-acid 8 in 10 mL of acetic acid and 0. 03 g of perchlo- 25% ammonium chloride in water and allowed to set-ric acid was hydrogenated at 80 C in the presence of tle. The THF solution was separated and concentrated0. 13 g of PtO2●3H2O at a normal pressure for 8 h. by atmospheric distillation and the product was crys-The catalyst was removed and the solution was con- tallized by adding dilute HCI. The resulting white solidcentrated to give white solid. After washing with w:was isolated by filtration and was dried at 70 C underter ,drying,0.92 g (92. 0% yield) of product(9) was vacuum to give 2.1 g of finasteride 1 in 96. 5% yield,obtained,mp> 310 C(lit.[2] mp> 310 C). MS: Mmp 251.5 C~253 C(in Refs.[2] and [3] mp 251 C319.13 C NMR (DMSO):174.850,170. 208,59. 783.~253 C). MS:M+ 372. High resolution MS: (M +2.8 Methyl 3- 0x0-4- aza-5a androstane- 17β-H)+ 373. 284 7 (req. 373. 285 5). I3C NMR (CDCl3):carboxylate(10)171. 75中国煤化工123.171， 59. 809，Toasuspensionof1.06g(~3.3mmol)ofthe57.608:YHCNMHG7.716.44. 084，above acid 9 in 10 mL of anhydrous methanol and 4.2 39. 605,335. 460,29. 576,29. 190,26. 133,mL of acetone dimethyl ketal was bubbled with dry 24. 429, 23.375,21. 397,13. 440,12. 155. The DEPThydrochloric gas for 4 h at room temperature,then re- spectroscopy of finasteride was shown in Fig. 1.fluxed for 2 h ;stood overnight. 0. 73g (66. 4 % yield)- 288TRANSACTIONS OF TIANJIN UNIVERS/TY Vol. 7 No.42001References[1] Rasmusson G H,Reynold G F,Utne T,et al. Azasteroids asinbibitors of rat prostatic 5a. reductase[J]. J Med Chem，1984.27:1690- 1701[2] Rasmusson G H, Reynold G F,Utne ,et al. Azasteroids :struc-ture- activity relationships for inhibition of 5a- reductase andandrogen receptor binding[J].J Med Chem, 1 986 , 29:2298 -2315[3] Rasmusson G H,Reynold G F.17beta-substituted-4-aza- 5al-pha- androstenones and their use as 5-alpha -reductase irhibitors[P]. EP 0155096, 1985- 09-18.[ 4] Heinzl s. Androgenetic alopecia : finasteride treated hair loss[J]. Med Monatsschr Pharm,1999 ,22(4):124- 127.[5]Tosti A. Piraccini B M. Finasteride and the hair cyele[J]. JAm Acad Dermatol ,2000.42(5 Pt 1):848- 849.180 160140 120 100 806040 20[6] Coltman CA Jr, Thompson IM Jr,Feigl P. Prostate cancerprevention trial (PCPT) update[J]. Eur Urol, 1999, 35 (5-6):544-547.[7] Li Xiaojun ,Chen Ligong，Fang Fang ,et al. Graphical synth-etic routes of finasteride[ J]. Chinese Journal of Pharmaceuti-Fig. 1 DEPT spectroscopy of finasteridecals ,2001,32(5):245- 247.非那甾胺的合成李效军，方芳, 王晓季，陈立功(天津大学药物科学与技术学院,天津300072)摘要:非那甾胺是一种底物竞争型5a还原酶抑制剂,用于良性前列腺增生的临床治疗.本文提出了一种新的合成方法,以孕烯醇酮为原料经10步反应制得了非那甾胺,即季铵化、甲氧基化、Oppenauer氧化、水解、氧化切断Ot双键、氨解环合.0*-双键加氢、酯化、A环1,2位脱氢和Bodroux反应.本方法避免了文献中昂贵试剂2,2' -二硫吡啶的使用.经质谱和/或核磁共振确定了所有化合物结构.以孕烯醇酮计,非那甾胺的总收率为13.67%.关键词:非那甾胺;全合成;孕烯醇酮中图分类号:R914.5文献标识码:A文章编号:1006- 4982(2001 )04 -0286- 04中国煤化工MHCNMH G289