Tacrolimus T 1961 1. L~~CH~ H3C-I 0 2.04. . benzene o w T~S-O,~,~ H3C-0 (XI) intermediate XM: OH 0 HO+OH + H3CYow CI&CI OH OH CH, CI H C 0 0 CH, ,'If K 0 0 L-arabinital a-ocetoxy- (XII) isobutyryl chloride 1 NoOCHJ, THF 1 L~-cH~, yII E. 2 Tbs-CI. THF 2 BF3 0(C2H& dm - , xm 1 sod~um methoxlde 2 boron trlfluorlde i 2 tert-butyldimethyl- 0 0 etherate sllyl chloride , mercury(ll) chloride. CH3 p-toluenesulfon~c ocid 2. HF. CH3CN 1. lithium diisopropylamide. methyl iodide 2. hydrogen fluoride in acetonitrile 3. benzyl trichloroacetimidate in trifluoromethansulfonic ocid Tbs & 0 0 (W 2. H3C-I , DMF 0 OH 0 3. HZ. Pd-C H C 0/CH3 . '0- - . - . 1. methanol, CH,O, 0, CH, sodium hydride CH,'CH, 2. methyl iodide 3. hydrogen 1962 T Tacrolimus I .To OH . 8 CH 2. Li+ B-H(< )3. THF CH3 1. pyridinium p-toluenesulfonate 2. L-selectride 3. boron trifluoride etherote. 1,3-proponedithiol 2, , 1 pyridine XVlI b 1. lithium olurninum hydride 2, triphenylphosphine, iodine tert-butyldimethyl- silyl trifluoro- rnethonesulfonote Tocrolimus: L~-CH, . MgBr2 v+XI -b butyllithium. magnesium bromide L;-CH, , THF _______, 2. ethylphosphonic acid bis(dirnethylamide), butyllithium 1. DCC 2. Zn, NH.,CI 3 Cl.,&cl . CH2C12. 0 DMSO (Swern oxidotion) H3C-0 2. zinc dust Boc 3. oxolyl chloride, dimethylsulfoxide Boc N-tert-butoxycorbo- nylpiperidine-2(S)- corboxylic acid Tacrolimus T 1963 1. L~-CH' 3. CH3COOH b XXItm 1 butyllithium Boc 2 methanol, [bis(trifluoro- acetoxy)~odo]benzene 3 acettc ac~d I Li+ H C N- CH3 ' Y Y , THF 0 CH,CH, XXll + ,0,).~/~~3 b XWI Drnb lithium diisopropylomide methyl 2-(2.4- dimethoxyben- zyloxy)acetate Tis-Ot,,, Boc Drnb, 0-CH3 1. 2,6-dimethylpyridine 2. N-methyl-2-chloro- pyridinium iodide 1. CF'COOH, THF, H,O " b XXVI 1. trifluoroocetic acid in THF 2. Dess-Martin periodinone (XXV) 1964 T Talampicillin 0 (selective deprotection) 2. XXV 3. HF. CH,CN 1. dichlorodicyonobenzoquinone 2. Dess-Mortin periodinone 3. HF in ocetonitrile Tocrolirnus Reference(s): production and a pharmaceutical composition; isolation: EP 184 162 (Fujisawa Pharmaceutical; appl. 11.6.1986; GB-prior. 5.2.1985, 1.4.1985). synthesis of FK-506: EP 378 318 (Fujisawa Pharmaceutical; appl. 18.7.1990; USA-prior. 1 1.1.1989, 30.6.1989). Ireland, R. et al.: I. Org. Chem. (JOCEAH) 61,6856 (1996). synthesis of intermediates: Danishefsky, S.J. et al.: J. Org. Chem. (JOCEAH) 55 (9), 2786 (1990). Schreiber, S.L. et al.: J. Am. Chem. Soc. (JACSAT) 112 (4), 5583 (1990). US 4 940 797 (Fujisawa Pharmaceutical; 10.7.1990; USA-prior. 23.3.1989) alternative synthesis: Shinkai, I. et al.: J. Am. Chem. Soc. (JACSAT) 111 (3), 1157 (1989). Shinkai, I. et al.: Tetrahedron Lett. (TELEAY) 29 (3), 281 (1988). Formulation(s): amp. 5 rnglml; cps. 1 mg, 5 mg Trade Name(s): D: Prograf (Fujisawa) GB: Prograf (Fujisawa) USA: Prograf (Fujisawa) F: Prograf (Fujisawa) J: Prograf (Fujisawa) Talampicillin ATC: JO 1 CAI 5 Use: antibiotic. antibacterial RN: 47747-56-8 MF: C2,H2,N,06S MW: 481.53 EINECS: 256-332-3 CN: [2S-[2a,5a,6~(S*)]]-6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-l- azabicyclo[3.2.0]heptane-2-carboxylic acid 1,3-dihydro-3-0x0-1-isobenzofuranyl ester Talinolol T 1965 monohydrochloride RN: 39878-70-1 MF: C,H,,N,O,S . HCl MW: 517.99 LD,,,: >I gkg (M, i.v.); >4 glkg (M, p.0.); 786 mg/kg (R, i.v.); >1 glkg (R, p.0.) methyl oceto- (1) acetate US 3 860 579 (Beecham; 14.1.1975; GB-prior. 9.6.1971). DAS 2 228 012 (Beecham; appl. 8.6.1972; GB-prior. 9.6.1971). DOS 2 228 255 (Beecham; appl. 9.6.1972; GB-prior. 9.6.1971). US3951 954(~arnanouchi;20.4.1976; J-prior 5.6.1971, 15.6.1971, 25.6.1971, 10.8.1971, 11.3.1972). DOS 2 225 149 (Yamanouchi; appl. 24.5.1972; J-prior. 5.6.1971, 15.6.1971,25.6.1971, 10.8.1971, 11.3.1972). Formulation(s): cps. 125 mg, 250 mg; tabl. 250 mg, 500 mg, 750 mg, 1 g (as hydrochloride) Trade Name(s): GB: Talpen (Beecham; 1975); Precillin (Edmond); wfm Talat (Polifarma); wfm wfm Talampicillina (Midy); J: Yamacillin (Beecham- I: Ausotal (Ausonia); wfm wfm Yamanouchi) Talinolol ATC: CO7AA Use: P-adrenoceptor antagonist, antihypertensive RN: 57460-41-0 MF: C20H33N307 MW: 363.50 LD,,: 30 mglkg (R, i.v.1 CN: (~)-N-cyclohexyl-W-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl]urea monohydrochloride RN: 38652-10-7 MF: C,oH1,N30, . HCI MW. 399.96 1966 T Talipexole 4-nitro- epichloro- phenol hydrin (+)-1-(4-nitrophenoxy)-2-hydroxy- 3-(tert-butylomino)propone (I) 1. Fe. HCI I 1 Talinolol OCN I + 2. cyclohexyl isocyanate Reference(s): DE 2 I00 323 (VEB Arzneimittelwerk Dresden, Ciba-Geigy; appl. 5.1.1971; CM-prior. 8.10.1970, 13.11.1970). US 4 120 978 (VEB Arzneirnittelwerk Dresden, Ciba-Geigy; 17.10.1978). DD 283 501 (VEB Arzneimittelwerk Dresden; appl. 29.7.1988). DD 283 499 (VEB Arzneimittelwerk Dresden; appl. 29.7.1988). DD 283 498 (VEB Arzneimittelwerk Dresden; appl. 29.7.1988). DD 283 496 (VEB Arzneirnittelwerk Dresden; appl. 29.7.1988). DD 264 114 (VEB Arzneimittelwerk Dresden; appl. 25.5.1987). 0 H H H synthesis of enantiomers: DD 285 343 (VEB Arzneimittelwerk Dresden; appl. 29.6.1989). Formulation(s): amp. 10 mg/5 ml; drg. 50 mg, 100 mg Trade Name(s): D: Cordanurn (ASTA Medica AW D) Talipexole (B-HT-920) Use: antiparkinsonian RN: 101626-70-4 MF: C,,,H,,N3S MW: 209.32 CN: 5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-6]azepin-2-amine dihydrochloride RN: 36085-73-1 MF: C,,H,,N,S .2HCI MW: 282.24 LD,,,: 455 mglkg (M, p.0.); 66 mglkg (R, i.v.); 403 mg/kg (R, p.0.) hexahydro- ally1 bromide 1 -ollylhexohydro- azepinone(4) 4H-azepin-"one 6 Tamoxifen T 1967 thiourea I Talipexole dihydrochloride I Reference(s): EP 195 888 (Thomae GmbH; appl. 1.10.1986; D-prior. 25.1.1985). DE 2 040 510 (Thomae GmbH, prior. 14.8.1970). DE 3 642 066 (Boehringer Ing., appl. 19.6.1987; prior. 9.12.1986). Anden, N E.; Grabowska-Anden, M.: J. Neural. Transm. (JNTMAH) 79 (3), 209-214 (1990). Formulation(s): tabl. 0.4 mg Trade Name(s): J: Domin (Boehringer Ing.) Tamoxifen ATC: L02BAO1 Use: antineoplastic, antiestrogen (palliative treatment of breast cancer) RN: 10540-29-1 MF: C,,H2,N0 MW: 371.52 EINECS: 234-1 18-0 LD,,: 2150 mglkg (M, p.0.); 4100 mglkg (R, p.0.) CN: (2)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine citrate (1:l) RN: 54965-24-1 MF: C,,H,,NO. C6H807 MW: 563.65 EINECS: 259-415-2 LD,,: 62.5 mglkg (M, i.v.); 3 100 mglkg (M, p.0.); 62.5 mg/kg (R, i.v.); 1190 mglkg (R, p.0.) 2-phenyl- 4-methoxyphenyl- butyrophenone (I) magnesium bromide (from 4-bromoonisole) 1. conc. HCI 2. pyridine hydrochloride . I1 (11) 2-(dimethylomino). ethyl chloride (111) cis.trans-tomoxifen (IV) 1968 T Tamoxifen crystollizotion from petroleum ether IV Tornoxifen H3C\ I + rfO~ -+ CO~C HC1. cZHati , H3C Mg Br 4-(2-dimethylomino- ethoxy)phenyl- mognesium bromide crystollizotion from petroleum ether N HO 0 . THF. 1. C2H50No 2. I11 Ti (from TiCI3 ond Zn) 0 + m propiophenone 4-hydroxy- benzophenone crystollizotion from petroleum ether IV Reference(s): US 4 536 516 (ICI) a,bHarper, M.J.K.; Walpole, A.L.: Nature (London) (NATUAS) 212, 87 (1966). GB 1013907 (ICI; appl. 13.9.1962). GB 1 064 629 (ICI; appl. 20.7.1965). separation of isomers: Bedford, G.R.; Richardson, D.N.: Nature (London) (NATIJAS) 212,733 (1966). DE 1 468 088 (ICI; appl. 5.9.1963; GB-prior. 13.9.1962, 21.8.1963). c EP 126 470 (Bristol-Myers; appl. 18.5.1984; USA-prior. 19.5.1983,22.2.1984). sinlilur process: EP 168 175 (Nat. Res. Dev. Corp.; appl. 19.1 1.1987; GB-prior. 12.6.1984, 11.6.1985). polymorphs of Lamoxifen citrate: Goldbcrg, I.; Becker, Y.: J. Pharm. Sci. (JPMSAE) 76,259 (1987). Tamsulosin hydrochloride T 1969 percutaneous administration; WO 85/03 228 (P. Mauvais-Jarvis and F. Kuttenn; appl. 21.12.1984; F-prior. 20.1.1984). GB 1013 907 (KT; appl. 13.9.1962; valid from 21.8.1963). GB 1064 629 (ICI; appl. 20.7.1965; valid from 4.3.1966). DE 1468 088 (ICI; appl. 5.9.1963; GB-prior. 13.9.1962, 21.8.1963). separation of isomers: Bedford, G.R.; Richardson, D.N.: Nature (London) (NATUAS) 212,733 (1966). Formulation(s): f. c. tabl. 10 mg, 20 mg, 30 rng, 40 mg; tabl. 10 mg, 20 mg, 30 mg, 40 mg (as citrate) Trade Nameis): D: duratamoxifen (durachemie) Jenoxifen (Jenapharm) Kessar (Farmitalia) Nolvadex (ICI-Pharma; 1976) Nourytan (Nourypharma) Tamobeta (betapharm) Tarnofen (RhGne-Poulenc Rorer) Tamox-GRY (Cry) Tamox-PUREN (Isis Puren) Tamoxasta (ASTA Medica AWD) Tamoxifen (Hexal; Heumann; ct-Arzncimittel; cell pharm; Aliud Pharma; biosyn; ratiopharm) F: Kessar (Pharmacia & Upjohn) Nolvadex (Zeneca; 1977) Oncotam (Mayoly- Spindler) Tarnofine (RhGne-Poulenc Rorer) GB: Nolvadex (Zeneca; 1973) Tamofen (Pharmacia & Upjohn; as citrate) I: Nolvadex (Zeneca) J: Nolvadex (Zeneca- Sumitomo Chem.; 198 1) USA: Kessar (Pharmacia & Upjohn) Ledertam (Wyeth-Lederle) Nolvadex (Zeneca; 1978) RN: 106463-17-6 MF: CZoH2RN20SS HC1 MW: 444.98 CN: (R)-5-[2-[[2-(2-Ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide monohydrochloride base RN: 106133-20-4 MF: C2,H2,N2O5S MW: 408.52 (+)-hydrochloride RN: 106463-19-8 MF: C2,,H2,N,0jS . HCI MW: 444.98 (+hydrochloride RN: 80223-99-0 MF: C20H28N205S . HC1 MW: 444.98 I. CISO~H 1. H,C~NH? 2. recrystallization, 2. CH30H benzene, ether 3. HZ, Pt02 o=s=o 4. HCI +I 0 1. chlorosulfonic 1. (R)-(+)-a-methyl- ocid 0 benzylamine 4-methoxyphenyl- acetone 5-ocetonyl-2-methoxy- benzenesulfonamide 1970 T Tamsulosin hydrochloride (R)-(-)-2-(4-methoxy-3- aminosulfonylphenyl)-1 - rnethylethylamine (U) 2. HCI (R)-(-)-2-(4-methoxy- bromo- phenyl)-l -methyl- ocetic ocid ethylamine Tomsulosin hydrochloride 1, 2. KZC03 DMF 1. CIS03H yH2 - 3. LiAIH, 2. NH,. CHCI, o=S=o 4. HCI Ill b hydrochloride 1. chlorosulfonic acid phenol H (R)-(+)-N-12-(3-omino- sulfonyl-4-methoxypheny1)- 1 -methylethyl]-2-bromo- acetamide Reference(s): a EP 257 787 (Yamanouchi; 2.3.1988; appl. 21.7.1987; J-prior. 21.7.1986) b JP 02 306 958 (Hokuriku; appl. 22.5.1988) synthesis of racemic Y M 1261 7: EP 34 432 (Yamanouchi, 26.8.1981 ; appl. 2.2.1981 ; J-prior. 8.2.1 980) Formulation(s): cps. 0.1 mg, 0.2 mg, 0.4 mg Trade Name(s): D: Aha (Boehringer F: Josir (Boehringer GB: Flomax (Boehringer Ingelheim) Ingelheirn) Ingelheim) - - OMNE (~am~noychi) - - - - Omix (Yamanouchi) - - - - - - - - - - . (R )-( +)-a-methyl- ocid 0 benzylamine 4-methoxyphenyl- acetone 5-ocetonyl-2-methoxy- benzenesulfonamide 1970 T Tamsulosin hydrochloride (R )-( - )-2 -( 4-methoxy- 3- aminosulfonylphenyl )-1 . 4774 7-5 6-8 MF: C2,H2,N,06S MW: 481.53 EINECS: 25 6-3 3 2-3 CN: [2S-[2a,5a,6~(S*)] ]-6 -[ (aminophenylacetyl)amino ]-3 ,3-dimethyl-7-oxo-4-thia-l- azabicyclo[3.2.0]heptane-2-carboxylic acid 1,3-dihydro- 3-0 x 0-1 -isobenzofuranyl. Talipexole (B-HT-920) Use: antiparkinsonian RN: 10162 6-7 0-4 MF: C,,,H,,N3S MW: 209.32 CN: 5,6,7,8-tetrahydro- 6-( 2-propenyl )-4 H-thiazolo[4, 5-6 ]azepin-2-amine dihydrochloride RN: 3608 5-7 3-1 MF: