Levocabastine L 1 I6 1 '33 S0Cl2 y3 b , NaOCH, tN TbH + Tos-CI \OH - Ill ' TOs-N~l phenylaceta- N-(2-hydroxy- ethyl)-2-hydroxy- propylarnine (-)-3-methyl-4- phenyl-1 -tasyl- 4-piperidinecarboxylic acid (IV) nitrile diasterorneric resolution by S-(-)-a-methylbenzylarnine KOH. ~~k~~ b b IV I. SOCI 2. HOa Tos-N e- [electrolytic detosylation] CH O v HN~~ benzyl (-)-3-methyl- 4-phenyl-4-piperidine- carboxylate (V1) I Levocarbastine Reference(s): US 4 369 184 (Janssen; 18.1.1983; prior. 24.1.1980,29.9.1980). EP 34 41 5 (Janssen; appl. 23.1.1981; USA-prior. 24.1.1980, 29.9.1980). 1162 L Levodopa Formulation(s): susp. 0.5 mg/ml (nasal spray, eye drops as hydrochloride) Trade Natne(s): D: Levophta (CIBA Vision1 F: Levophta (Chauvin) Livostin (Janssen) Winzer; as hydrochloride) GB: Livostin (CIBA Vision) Livocab (Janssen-Cilag) I: Levostab (Formenti) Levodopa ATC: N04BAOl Use: antiparkinsonian RN: 59-92-7 MF: C,H,,NO, MW: 197.19 EINECS: 200-445-2 CN: 3-hydroxy-L-tyrosine enzymatic hydroxylotion H 0 L-tyrosine (I) Levodopa H2OZ. FeSO,, hu I hydrogen peroxide vanillin (11) hydantoin racemote resolution -b @ Monsanto process: n + rCooH + ,j, J1 NH2 H3C 0 CH, H3C J. 0 CH3 glycine (In) Levodopa L 1163 3-rnethoxycinnarnic ocid (IV) a-ocetarnido-4-acetoxy- 3-rnethoxycinnornic ocid (V) y3 Hz, cotoiyst from A ond B COOH HBr v b 0 A: 1,5-cyclooctodienylrhodium chloride 0: (+)-cyclohexylrnethyl(2-methoxyphenyl)phosphine piperonol (W diethyl ocetornidomalonote Reference(s): a Amao, S. et al.: Sankyo Kenkyusho Nempo (SKKNAJ) 23,249 (1971). Sih, C.J. et al.: J. Am. Chem. Soc. (JACSAT) 91,6204 (1969). b Waser, E.; Lewandowski, M.: Helv. Chim. Acta (HCACAV) 4,657 (1921). hydronyla~ion with benzoyl peroxide: DAS 2 026 952 (Schering; appl. 28.5.1970). c Bretschneider, H. et al.: Helv. Chim. Acta (HCACAV) 56, 2857 (1973). DAS 2 023 459 (Roche; appl. 13.5.1970; CH-prior. 14.5.1969). DAS 2 023 460 (Roche; appl. 13.5.1970; CH-prior. 14.5.1969). DAS 2 023 461 (Roche; appl. 13.5.1970; CH-prior. 14.5.1969). similar method: DAS 2 026 952 (Schering AG; appl. 28.5.1970). d US 2 605 282 (Dow; 1952; appl. 1949). racemate resolu~ion of ~~-N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)alanine with dehydroabietylamine: DOS 1 964 420 (Roche; appl. 23.12.1969; CH-prior. 27.12.1968). 1164 L Levodopa racemate resolution of DL-N-acetyl-3-(4-acetoxy-3-methoxypheny1)alanine with (-)-a-phenylethylamine: DOS 2 052 953 (Egyt; appl. 28.10.1970; H-prior. 28.10.1969). with (+)-threo-2-amino-l-(4-nitrophenyl)-l,3-propanediol: DOS 2 052 995 (Egyt; appl. 28.10.1970; H-prior. 28.10.1969). alternative synthesis via 2,5 dioxopiperazine: Losse, G. et al.: J. Prakt. Chem. (JPCEAO) 21, 32 (1963). e US 4 005 127 (Monsanto; 25.1.1977; prior. 8.3.1971). DAS 2 123 063 (Monsanto; appl. 10.5.1971; USA-prior. 11.5.1970, 8.3.1971). DAS 2 210 938 (Monsanto; appl. 7.3.1972; USA-prior. 8.3.1971). US 4 124 533 (Monsanto; 7.1 1.1978; prior. 9.9.1968, 11.5.1970, 8.3.1971, 17.3.1975). Knowles, W.S. et al.: J. Am. Chem. Soc. (JACSAT) 97,2567 (1975). Vineyard, B.D. et al.: J. Am. Chem. Soc. (JACSAT) 99,5946 (1977). similar method: DOS 2 161 200 (IFR; appl. 9.12.1971; F-prior. 10.12.1970). f Yamada, S. et al.: Chem. Pharm. Bull. (CPBTAL) 10,680, 688,693 (1963). alternative syntheses from piperonal: Mori, K.: Nippon Kagaku Zasshi (NPKZAZ) 81,464 (1960). Barry, R.H. et al.: J. Am. Chem. Soc. (JACSAT) 70,693 (1948). other methods for racemate resolution of DL-dopa or its derivatives: US 3 405 159 (Merck & Co.; 8.10.1968; appl. 17.1 1.1964). CH 5 11 774 (Ajinomoto; appl. 22.4.1970; J-prior. 23.4.1969). Yamada, S. et al.: J. Org. Chem. (JOCEAH) 40, 3360 (1975). racemate resolution of DL-N-benzoyldopa with cinchonine: DOS 1 963 992 (Dynamit Nobel; appl. 20.12.1969). racemization of D-N-benzoyldopa with acetanhydride: DOS 1 963 991 (Dynamit Nobel; appl. 20.12.1969). racemization of D-dopa by thermic treatment: DAS 2 126 049 (Dynamit Nobel; appl. 26.5.1971). fermentative and enzymatic methods: from 3,4-dihydroxyphenylpyruvic acid by trunsamination by means of microorganisms: DOS 2 041 418 (Anm. 14.8.1970; J-prior. 16.8.1969). by means of transaminase from Alcaligenes faecalis (IAM 1015): DAS 2 148 953 (Nisshin Flour Milling; appl. 30.9.197 1; J-prior. 30.9.1970, 1.6.197 1, 19.8.1971). from pyrocatechol, pyruvic acid and ammonium salts by means of P-tyrosinase: DAS 2 152 548 (Ajinomoto; appl. 21.10.1971; J-prior. 21.10.1970,2.11.1970,30.12.1970). enzymatic resolution of DL-N-phenylaccty 1-3-(3,4-methylenedioxypheny1)alanine or DL-N-phenylacetyl-3-(3,4- dimethoxypheny1)alanine or DL-N-phenylacety 1-3-(3,4-dihydroxypheny1)-alanine by means of Escherichia coli- arylase: DOS 2 100 445 (Astra; appl. 7.1.1971; S-prior. 19.1.1970.25.6.1970). isolation from the seed meal of fodder beans or vetch pods: US 3 253 023 (Dow; 24.5.1966; appl. 27.9.1963). combination with carbidopa: US 3 769 424 (Merck & Co.; 30.10.1973; prior. 1.10.1968,23.6.1969, 1.10.1970). combination with etoperidone and trazodone: US 4 131 675 (Angelini Francesco; 26.12.1978; appl. 9.2.1978). Formulation(s): cps. 125 mg, 200 mg, 250 mg, 500 mg; tabl. 100 mg, 200 mg, 500 mg Trade Name(s): D: Dopaflex (medphano) Madopar (Roche)-comb. with benserazide Nacom (Du Pont Pharma)- comb. with carbidopa Levofloxacin L 1165 numerous generics F: Modopar (Roche)-comb. with benserazide Sinernet (Du Pont Pharma)- I: comb. with carbidopa GB: Madopar (Roche)-comb. with benserazide Sinemet (Merck Sharp & Dohme)-comb. with carbidopa Larodopa (Roche) Madopar (Roche)-comb. with benserazide Sinemet (Du Pont)-comb. with carbidopa Doparl (Kyowa) Dopasol (Daiichi) Dopaston (Sankyo) Larodopa (Roche) Neodopaston (Sankyo). comb. with carbidopa USA: Larodopa (Roche) Sinemet (Du Pont)-comb. with carbidopa generic Levofloxacin ATC: JOIMAI~ ((S)-Ofloxacin; DR-3355; HR-355; RWJ-25213) Use: antibacterial RN: 100986-85-4 MF: C,,H,FN,O, MW: 361.37 LD,,: 1803 mgkg (M, p.0.); 1478 rngkg (R, p.0.) CN: (S)-9-fluoro-2,3-dihydro-3-methy1-10-(4-~nethy1-1-pipcraziny1)-7-oxo-7H-pyrido[1,2,3-de]-1,4- benzoxazine-6-carboxylic acid hydrate (2:l) RN: 138 199-71-0 MF: C1,HmFN304. 1RH20 MW: 740.76 0 I 3. CrO3 OH KXO DMF. ,, - F n2d4. ocetone F F CI 2,3-difluoro-6- epichloro- nitrophenol (I) hydrin 2.3-difluoro- 6-nitrophenyl oxironylmethyl ether 1. Hz, Roney-Ni, C2HSOH H3C- 3 H3cIohodH3 0 0 105-115 OC b ;&?XjCH3 2. diethyl ethoxymethylene- rnolonote (111) OdH3 H3C,0 0 1 -(2.3-difluoro- 6-nitrophenoxy)- 3-methoxy-2- proponone (11) 1. polyphosphote. diethyl [(7.8-difluoro- 3-methoxymethyl-2,3- dihydro-4H-1.4-benz- oxozin-4-yl)methylene]- molonote (IV) FS F LCH, 0 0 (?)-ethyl 9.10-difluoro- 3-hydroxymethyl-7-0~0- 2,3-dihydro-7H-pyrido- [I ,2.3-de]-1.4-benzoxozine 6-corboxylote (V) 1 I66 L Levofloxacin 3.5-dinitro- benzoyl chloride (?)-ethyl 9.1 O-difluoro- 3-(3.5-dinitrobenzoyl- oxymethy1)-7-0x0-2.3- dihydro7H-pyrido- [I ,2.3-de]-1.4-benzoxo- zine-6-corboxylote (VI) DMF, 70-80 "C OvCH3 - 0 0 phosphonium iodide (-)-ethyl 9.1 O-difluoro- 3-hydroxymethyl-7-0~0- 2,3-dihydro-7H-pyrido- [1.2.3-de]-1.4-benzoxo- zine-6-corboxylote (VII) 1. HSn[(CH2)3-CH,]3, C2HSOH. 50-60 OC 0yCH3 2. CH3COOH, HCI VIU 1. tributyltin hydride 'yy-), F COOH 0 7-0x0-2.3-dihydro-7H-pyrido- (S)-9.10-difluoro-3-methyl- [I .2.3-de]-1.4-benzoxazine-6- corboxylic acid (M) N-methyl- piperozine Levofloxacin Levofloxacin L 1167 1. K2C03, ocetone. KL 1 2. Hz. Raney-Ni. CH30Y 1 + cl/\rf'0 CH3 - 0 (?)-3-acetoxymethyl-7.8- difluoro-2,3-dihydro-4H- 1.4-benzoxazine (X) hydrolytic enzyme 1. SOCI~, 50-60 oc 0yCH3 optical resolution N H 2.DMS0, NaH x- - (-)-7.8-difluoro-2.3- dihydro-3-methyl-4H- 1.4-benzoxazine (XI) 0yCH3 H~sO,. 50-60 OC 2. CH3COOH, HCI F OdH3 H3C,0 0 XI1 chloride 1. pyridine. CH2C12 2. separation of diastereomers b 2.3.4.5-tetrafluoro- monoethyl benzayl chloride malonate ethyl 2.3,4,5-tetra- fluorobenzoylacetate (XIV) 1. NOH. DMSO 2. KOH. H20. THF. 65-70 OC XV b IX Levofloxacin 0 2. H2. 107. Pd-C, C2H50H XVI b 1. rnethonesulfonyl chloride XI + W -+ 1X -+ Levofloxocin LI a-c EP 206 283 (Daiichi Seiyaku; appl. 20.6.1986; J-prior. 20.6.1985, ll.lO.l985,28.l.l986). d US 4 777 253 (Abbott Labs.; 11.10.1980; appl. 25.4.1986; USA-prior. 25.4.1986). DE 3 543 513 (Bayer AG; appl. 10.12.1985; D-prior. 10.12.1985). e EP 368 410 (Gist-Brocades; appl. 6.1 1.1989; EP-prior. 7.1 I .l988). Atarashi, S. et al.: Chem. Pharm. Bull. (CPBTAL) 35 (3, 1896 (1987). preparation of 2,3-difluoro-6-nitrophenol: O'Neill, P.M et al.: J. Med. Chem. (JMCMAR) 37 (9), 1362 (1994). Hayakawa, I.; Hiramitsu, T.; Tanaka, Y.: Chem. Pharm. Bull. (CPBTAL) 32 (12), 4907 (1984). preparation of intermediate XI: JP 05 068 577 (Mercian Corp.; appl. 11.12.1990; J-prior. 1 1.12.1990). synergistic combination with azidothymidine: WO 9 013 542 (Daiichi Pharm.; appl. 27.4.1990; J-prior. 23.2.1990). topical formulation: EP 274 7 14 (Daiichi Seiyaku; appl. 18.12.1987; J-prior. 18.12.1987). liposomes with increased retention: WO 9 526 185 (Daiichi Pharm.; appl. 27.3.1995; J-prior. 28.3.1994). Formulation(s): gran. 100 mglg; tabl. 100 mg, 250 mg; vial 5 mg/ml, 25 mglml Trade Name(s): D: Tavanic (Hoechst Marion J: Cravit (Daiichi Seiyaku) Roussel; 1998) USA: Levaquin (Ortho-McNeil) Levomepromazine (Laevomepromazine; Methotrimeprazine) ATC: N05AA02 Use: neuroleptic RN: 60-99-1 MF: C,,H,,N,OS MW: 328.48 EINECS: 200-495-5 LD,,,: 39 mgkg (M, i.v.); 370 mgkg (M, p.0.); 1100 mgkg (R, p.0.) CN: (R)-2-methoxy-N,N,P-trimethyl- I OH-phenothiazine- 10-propanamine Levonorgestrel L 1 169 monohydrochloride RN: 1236-99-3 MF: C,,H,N,OS . HCl MW: 364.94 EINECS: 214-978-3 LD,,: 75 mglkg (M, i.v.); 380 mglkg (M, p.0.) maleate (1:l) RN: 7104-38-3 MF: C,,H2,N20S. C4H404 MW: 444.55 EINECS: 230-412-8 H CH,?~~ NoNH2 &'\CH3 sodium ' CI omide Z-methoxy- 3-dimethylomino- phenothiazine 2-methylpropyl chloride 1 Levomepromozine I (+)-mepromozine (I) Reference(s): US 2 837 518 (RhBne-Poulenc; 1958; F-prior. 1954). Dl3 1 034 638 (RhBne-Poulenc; appl. 1955; F-prior. 1954). Formulation(s): amp. 25 mg, 200 mg (as hydrochloride); sol. 40 mg/ml; tabl. 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg Trade Name(s): D: Neurocil (Bayer Vital) I: Nozinan (RhGne-Poulenc Levaru (Mohan) Tisercin (Thiemann) Rorer) Levomezine (Toho) F: Nozinan (Specia) J: Dedoran (Shionogi) Levotomin (Yoshitomi) GB: Nozinan (Link) Hirnamin (Shionogi; as Sofmin (Dainippon) maleate) USA: Levoprome (Immunex) Levonorgestrel (D-Norgestrel; Dexnorgestrel) ATC: G03AC03 Use: progestogen RN: 797-63-7 MF: C2,H2,0, MW: 312.45 EINECS: 212-349-8 CN: (17a)-13-ethy1-17-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one 6-methoxy- vinylmognesium 1 -tetralone chloride cyclopentonedione 1170 L Levonorgestrel socchoromyces pyridine uvorum 2~~~0- 11 ______+ 1. Hz, Pd-C 2. KOH, CH30H &IcH3 3. Li. NH3, b 2. potossium hydroxide H C 3. lithium, oniline '0 (11) (W 2. UCECH 3. HCI nr 1. oluminum triisopropylote. methyl ethyl ketone 2, lithium ocetylenide Levonorgestrel u Reference(s): Rufer, C. el al.: Justus Liebigs Ann. Chem. (JLACBF) 702,141 (1967). alternative syntheses: DOS 1 806 410 (Hoffmann-La Roche; appl. 31.10.1968; USA-prior. 2.11.1967). Smith, H. et al.: J. Chem. Soc. (JCSOA9) 1964,4472. ethynylation methods: DD 1 14 807 (Reihe, Kutz; appl. 1 1.10.1974). DE 2 030 056 (Schering AG; appl. 13.7.1970). use us contraceptive: DOS 1 922 005 (Schering AG; appl. 24.4.1969). combination with 17a-ethynylcstradiol us contraceptive: DOS 2 218 831 (Schering AG; appl. 14.4.1972). DOS 2 335 265 (Schering AG; appl. 30.1.1975). DAS 2 365 103 (Schering AG; appl. 21.12.1973). DOS 2 43 1 704 (Asche; appl. 2.7.1974). intrauterine anticonception: DOS 2 36 1 206 (Schering AG; appl. 6.1 2.1973). pharmaceutical formulation: DOS 2 432 925 (Schering AG; appl. 5.7.1974). DOS 2 449 865 (Schering AG; appl. 17.10.1974). Formulation(s): drg. 0.03 mg, 0.1 mg, 0.15 mg, 0.25 mg; pessaries 52 mg Trade Name(s): D: Micro-30-Wyeth (Wyeth) Mirena Intrauterinpessar Microlut (Schering) (Schering) numerous combination preparations . [(7.8-difluoro- 3-methoxymethyl-2, 3- dihydro-4H-1.4-benz- oxozin-4-yl)methylene ]- molonote (IV) FS F LCH, 0 0 (?)-ethyl 9.10-difluoro- 3-hydroxymethyl- 7-0 ~ 0- 2,3-dihydro-7H-pyrido- [I ,2.3-de ]-1 .4-benzoxozine. (R, p.0.) CN: (S )-9 -fluoro-2,3-dihydro-3-methy 1-1 0-( 4-~ nethy 1-1 -pipcraziny1 )-7 -oxo-7H-pyrido[1,2,3-de ]-1 , 4- benzoxazine-6-carboxylic acid hydrate (2:l) RN: 138 19 9-7 1-0 MF: C1,HmFN304 ,2.3-de ]-1 .4-benzoxo- zine-6-corboxylote (VI) DMF, 7 0-8 0 "C OvCH3 - 0 0 phosphonium iodide (-) -ethyl 9.1 O-difluoro- 3-hydroxymethyl- 7-0 ~ 0- 2,3-dihydro-7H-pyrido- [1.2.3-de ]-1 .4-benzoxo-