Naproxen N 1401 (5)-2-(5-bromo-6- methoxy-2-nophthyl). propanoic acid (XII) @ Stereospecific Syntex process: 1. NaOH ethyl (5)-loctate mesyl 0 chloride II Ms: -S-CH3 II 0 (IRC-50s resin), 115- 120 OC cH3 H3C XV 0x0~ process review: Harrington, P.J.; Lodewijk, E.: Organic Process Res. & Dev. 1,72 (1997). Harrison, J.T. et al.: J. Med. Chem. (JMCMAR) 13, 203 (1970). a US 3 896 157 (Syntex; 22.7.1975; prior. 13.1.1967,7.12.1967,4.11.1971). US 3 904 682 (Syntex; 9.9.1975; prior. 13.1.1967, 7.12.1967,24.3.1969, 31.8.1971, 21.6.1973). US 3 978 116 (Syntex; 31.8.1976; prior. 13.1.1967,7.12.1967,4.11.1971). US 3 978 124 (Syntex; 31.8.1976; prior. 13.1.1967,7.12.1967,4.11.1971). US 3 998 966 (Syntex; prior. 4.1 1.1971). US 4 001 301 (Syntex; 4.1.1977; prior. 4.11.1971). US 4 009 197 (Syntex; 22.2.1977; prior. 13.1.1967). DAS 1 668 654 (Syntex; appl. 8.1.1968; USA-prior. 13.1.1967; 7.12.1967). improved racemate resolution with cinchonidine: DAS 2 319 245 (Syntex; appl. 16.4.1973; USA-prior. 21.4.1972, 11.4.1973). racemizatiort: DAS 2 008 272 (Syntex; appl. 23.2.1970; USA-prior. 24.3.1969). US 3 663 584 (Syntex; 16.5.1972; appl. 4.12.1970). similar process with Cu-compound: US 3 658 863 (Syntex; 25.4.1972; appl. 30.9.1969). similar process with Cd-compound: IJS 3 694 476 (Syntex; 26.9.1972; appl. 4.12.1970). DOS 2 805 488 (Syntex; appl. 9.2.1978; USA-prior. 16.2.1977, 19.12.1977). resolution with N-alkyl-D-glucamines: US 4 515 81 1 (Syntex; 7.5.1985; USA-prior. 6.7.1979, 26.11.1979). EP 7 116 (Syntex; appl. 17.7.1979; CH-prior. 19.7.1978). DOS 3 025 448 (Syntex; appl. 4.7.1980; USA-prior. 6.7.1979, 26.1 1.1979). Ohta, T. et al.: J. Org. Chem. (JOCEAH) 52, 3174 (1987). DOS 2 919 919 (Montedison; appl. 17.5.1979; I-prior. 22.5.1978). US 4 239 9 14 (Montedison; 16.12.1980; I-prior. 22.5.1978). electrocurboxylation of 2-acetyl-6-methoxynaphthalene: Chan, AS. et al.: J. Org. Chem. (JOCEAH) 60,742 (1995). naphthacrylic acid via corresponding cyanohydrins: US 3 637 767 (Syntex; 25.1.1972; appl. 30.7.1968). Giordano, C. et al.: Tetrahedron (TETRAB) 45,4243 (1989). US 4 579 968 (Zambon; 1.4.1986; I-prior. 24.2.1984). US 4 697 036 (Zambon; 29.9.1987; I-prior. 6.8.1984). US 4 810 819 (Zambon; 7.3.1989; appl. 5.8.1987; USA-prior. 5.4.1985). US 4 855 464 (Zambon; 29.9.1987; I-prior. 6.8.1984). US 4 888 433 (Zambon; 29.9.1987; I-prior. 6.8.1984). preparation of 2-propionylnaphthalene: EP 176 142 (Blaschim; appl. 16.9.1985; I-prior. 24.9.1984, 17.5.1985). EP 301 31 1 (Zambon; appl. 12.7.1988; I-prior. 28.7.1987). US 4 605 758 (Syntex; 12.8.1986; prior. 11.12.1981, 23.4.1984). US 4 749 804 (Syntex; 7.6.1988; prior. 11.12.1981, 23.4.1984, 10.6.1986). US 4 912 254 (Syntex; 27.3.1990; prior. 11.12.1981,23.4.1984, 10.6.1986, 6.5.1988). alternative syntheses: DAS 1 934 460 (Syntex; appl. 8.7.1969; USA-prior. 30.7.1968). US 3 637 767 (Syntex; 25.1.1972; appl. 30.7.1968). DAS 1 793 825 (Syntex; appl. 8.1.1968; USA-prior. 13.1.1967,7.12.1967). resolution with dehydroabietylaminc: DAS 2 339 765 (Syntex; appl. 6.8.1973; USA-prior. 10.8.1972). resolution with (S)-a-phenylethylamine: US 4 546 201 (Blaschim; 8.10.1985; I-prior. 27.7.1983) enzymatic cleavage of esters of racemic naproxen: US 4 857 462 (Boehringer Mannh.; 15.8.1989; D-prior. 16.12.1983). EP 195 717 (Montedison; appl. 17.3.1986; I-prior. 22.3.1985). EP 233 656 (Gist-Brocades; appl. 6.1.1987; GB-prior. 7.1 .l986). EP 330 217 (1st. Guido Donegani; appl. 24.2.1989; I-prior. 25.2.1988,29.7.1988). Formulation(s): f. c. tabl. 250 mg, 500 mg, 1000 mg; suppos. 250 mg, 500 mg; susp. 125 mg15 ml, 250 mg/5 ml; tabl. 250 mg, 375 mg, 500 mg, 750 mg (as acid); f. c. tabl. 550 mg; tabl. 275 mg, 550 mg, 375 mg, 500 mg (as sodium salt) Trade Namefs): D: Apranax (Roche; Syntex) Naprosyne (Cipharm; I: Aperdan (ABC Dysmenalgit (Krewel 1975) Farmaceutici)-comb. Meuselbach) GB: Napratec (Searle) Artroxen (Errekappa Proxen (Roche; Syntex; Naprosyn (Roche; 1973) Euroter.) 1975) Nycopren (Ardern) F: Apranax (Roche) Synflex (Roche) Naratriptan N 1403 Axer Alfa (Alfa Wassermann; as sodium salt) Floginax (Teofarma) Flogogin (Angelini; as sodium salt) Floxalin (Salus Research; as sodium salt) Gibinap (Metafarm) Gibixen (Metafarm) Laser (Tosi-Novara) Leniartril (Sancarlo) Naprius (Aesculapius-Rs) Naprorex (Lampugnani) Naprosyn (Recordati) Neoblimon (Guidotti) Nitens (Pulitzer)-comb. Numidan (Therabel Pharma)-comb. Piproxen (Nuovo ISM)- J: comb. USA: Prexan (Lafare) Primeral (Master Pharma; as sodium salt) Proxine (Del Saz & Filippini) Synalgo (Geymonat) Synflex (Recordati; as sodium salt) Ticoflex (Farma Uno) Xenar (Alfa Wassermann) Naixan (Tanabe) Anaprox (Roche) Naprosyn (Roche; 1976) generics Naratriptan (GR-85548) ATC: N02CC02 Use: antimigraine agent, 5-HT,-agonist RN: 121 679-13-8 MF: C,,HzsN30zS MW: 335.47 CN: N-methyl-3-(l-methyl-4-piperidinyl)-lH-indole-5-ethanesulfonamide hydrochloride RN: 121 679- 19-4 MF: C,,H,,N,O,S . xHC1 MW: unspecified monohy drochloride RN: 143388-64-1 MF: C,,H2,N302S . HCl MW: 371.93 0 KOH, CHJOH. 20 "C 1 -methyl-4- piperidone (11) " \\ A\ DMF 110 "C 111 + H3C@S\ CH,- u n pollodium ocetote (V) ,I - tri-p-tolylphosphine (VI) N-methylvinyl- sulfonomide (N) 1404 N Naratriptan Hz. Pd-C. DMF, HzO VII - I Naratripton KOH. H 1. N. v. VI DMF. 110 "C 2. H,, Pd-C. or: H 0 KOH. CH,OH, A I-hydroxy- 1 -methyl- piperidine H 1. 11 . KOH, A IV. v. VI I b 1. potassium hydroxide 2. hydrogen Natamycin N 1405 1. 2N HCI, 20 OC H 2. CHCI,. polyphosphate ester OH'% 'b CH3 2-(4-hydrazinophenyl)- 2-(1 -methyl- N-methylethanesulfon- 4-piperidinyl). omide acetaldehyde wo 9 509 166 (Glaxo; appl. 6.4.1995; GB-prior. 29.9.1993). EP 303 507 (Glaxo; appl. 15.2.1989; GB-prior. 13.8.1987, 14.6.1988, 17.6.1988). Fomtulation(s): tabl. 2.5 mg (as monohydrochloride) Trade Name(s): D: Naramig (Glaxo Wellcornel Cascan) Natamycin (Pimaricin) ATC: A01 AB 10; A07AA03; DOlAA02; G01AA02; S01AA10 Use: fungicidal antibiotic RN: 7681-93-8 MF: C,,H,,NO,, MW: 665.73 EINECS: 231-683-5 LD,,: >5 gkg (M, i.v.); 1500 mgkg (M, p.0.); 36 mglkg (R, i.v.); 2730 mgkg (R, p.0.); 18 mgkg (dog, i.v.); >300 mgkg (dog, p.0.) CN: [I R-(1 R*,3S*,5R*,7R*,8E,12R*, 14E,16E,18E,20E,22R*,24S*,25R*,26S*)]-22-[(3-amino-3,6-dideoxy-~- D-mannopyranosyl)oxy]-1 ,3,26-trihydroxy- l2-methyl-lO-oxo-6,11,28-trioxatricyclo[22.3.1.0'~7]octacosa- 8,14,16,18,20-pentaene-25-carboxylic acid Notomycin From fermentation solutions of Streptomyces natalensis. Reference (s): GB 844 289 (Konigl. Niederl. Gist- & Spiritusfabr.; appl. 1957; NL-prior. 1956). GB 846 933 (American Cyanamid; appl. 1957; USA-prior. 1956). Fomtulation(s): cream 2 gllOO g; drg. 100 mg; ointment 10 mglg; tabl. 10 mg Trade Name(s): D: Deronga (Galderma) Pima Biciron (S & K Pharma) Pimafucin (Galderma) F: Pimafucine (Beytout); wfm Pimafucort (Yamanouchi)- Pimafucine (Duphar); wfm comb. Pimafucort (Beytout); wfm 1406 N Nateglinide GB: Pimafucin (Brocades); wfm I: Natafucin (Yamanouchi J: Pimafucin (Toni)-comb. Pharma) USA: Myprozine (Lederle); wfm Nateglinide Use: hypoglycemic agent (A 4 1 66; Ay 4 16; SDT-DJN 608) RN: 105816-04-4 MF: C,,H,NO, MW: 317.43 CN: trans-N-[[4-(l-Methylethyl)cyclohexyl]-carbonyl]-D-phenylalanine (S)-(-)-perillic ocid HOOC 1. HZ. Pt02. CH3COOH 2. PCIS , Clb /J,,,(CH~ CH3 trons-4-isapropylcyclo- hexanecarbonyl chloride (1) 107; oq. NaOH, acetone Noteglinide I curninic ocid 1. NOH. 1 50°C 2.2N NaOH, CH30H 3. HC, recrystallization I1 - O-phcnylalanine methyl ester HOOC ~lft~~C HI CH3 trons-4-isopmpyl- cyclohexanecarboxylic acid 0 HO-N> . DCC, CHCI, 0 2. 2N NoOH. CH,OH Nateglinide 1. N-hydroxysuccinirnide EP 196 222 (Ajinomoto; appl. 26.3.1986; J-prior. 27.3.1985). Nazasetron N 1407 preparation of I: JP 7 017 899 (Ajinomoto; appl. 1.7.1993). stable crystals: US 5 463 11 6 (Ajinomoto; 3 1 .lo. 1999; J-prior. 30.7.1991). tablet formulation: WO 9 822 105 (Ajinomoto; appl. 14.1 1.1997; J-prior. 15.1 1.1996). Fornwlation(s): tabl. 30 mg Trade Name(s): J: Starlix (Ajinomoto, 1999) Nazasetron (Y-25 130) ATC: A04AA Use: anti-emetic, 5-HT3-antagonist RN: 123040-69-7 MF: C17H20CIN,03 MW. 349.82 CN: (~)-N-l-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8- carboxamide monohydrochloride RN: 141922-90-9 MF: CI7H2,C1N3O3 . HCl MW: 386.28 (-)-enantiomer RN: 123040-95-9 MF: C17H20CIN303 MW: 349.82 (-)-enantiomer monohydrochloride RN: 123040-96-0 MF: C,,Hz0CIN3O3. HCI MW: 386.28 (+)-enantiomer RN: 123040-93-7 MF: C17H,ClN,03 MW: 349.82 (+)-enantiomer hydrochloride RN: 123040-94-8 MF: C17H,C1N,03. HCI MW: 386.28 methyl 5-chloro- salicylate methyl 5-chloro-3- methyl 3-omino- nitrosolicylote 5-chlorosolicylote (1) ,o 0 1. K2C03, DMF t4(C2H5)> CHCll H3C 2. H C-I. KOtBu I + 3 1, , Cl '10 brornoocetyl chloride methyl 3-(2-bromo- ocetylomino)-5-chloro- salicylote 1408 N Nebivolol 6-chloro-3.4- dihydro-4-methyl- 3-0x0-2H-1.4-benz- oxazine-8- carboxylic ocid (U) 6-chloro-3.4- dihydro-4-methyl- 3-0x0-2H-1,4-benz- oxozine-8- corbonyl chloride @I) 3-amino- 1 Nazosetron - I quinuclidine - Reference(s): EP 3 13 393 (Yoshitomi; appl. 21.10.1988; J-prior. 22.10.1987,25.12.1987, 13.1.1988). stable crystalline structure of (+)-enantiomer: JP 07 070 120 (Yoshitomi; appl. 5.7.1994; I-prior. 5.7.1993). medical use: JP 08 027 001 (Yoshitomi; J-prior. 13.7.1994). JP 08 027 000 (Yoshitomi; J-prior. 13.7.1994). JP 08 026 999 (Yoshitomi; J-prior. 12.7.1994). WO 9 601 630 (Yoshilomi; appl. 7.7.1995; J-prior. 12.7.1994). suppositoryformulation: JP 06 305 969 (Yoshitomi; appl. 27.4.1993; J-prior. 27.4.1993). light-stabilized injection solution: WO 9 425 032 (Yoshitomi; appl. 25.4.1995; J-prior. 28.4.1994). Formulation(s): amp. for injection 10 mg/2 ml Trade Name(s): J: Serotone (Yoshitomi; TobaccoIGreen Cross) Nebivolol ATC: C07AB12 (ME-3255; R-65824; R-67555 as hydrochloride) Use: antihypertensive, fl,-adrenergic blocker RN: 1 18457- 14-0 MF: C22H25F2N04 MW: 405.44 CN: [2R*[R*[R*(S*)]]]-a,a'-~iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride RN: 152520-56-4 MF: C22H25F2N04 . HC1 MW: 441.90 Nedaplatin N 1409 0 0 COOH 3. H3C\r~~9CH3 , toluene J&Y CH, H CH, F 2. 1,l'-corbonylbis- F n CUHO u (1 H-imidozole) 6-fluoro-4-oxo- 3. bis(2-rnethylpropyl)- 6-fluoro-3.4-dihydro- benzopyron-2- olurninum hydride 2H-benzopyran-2- carboxylic ocid carboxaldehyde (I) 6-fluoro-3.4-dihydro- 2-oxiranyl-2H-1- benzopyran Nebivolol I Reference(s): EP 145 067 (Janssen Pharm.; appl. 22.1 1.1984; USA-prior. 5.1 2.1983). Formulation(s): tabl. 5 mg (as hydrochloride) Trade Name(s): D: Nebilet (Berlin-Chemie) ' Nedaplatin (S 254) Use: antineoplastic platinum complex RN: 95734-82-0 MF: C2H8N203Pt MW: 303.18 LD,,: 20 mgkg (R, i. v.); 44.1 mgkg (M, i. v.); 4 mgkg (dog, i. v.) CN: (~~-4-3)-~iammine[h~drox~acetato(2-)-O',0~]platinum H3NL pH3 AgNO, H3N\p:NH3 onion exchange resin H3N\ dNH3 Pt 4 / \ _____3 Pt CI/ \CI 02N-0 0-NO2 HO' \OH cisplatin (q. v.) diarnrnineplatinurn nitrate 1410 N Nedocromil glycolic acid Nedaplotin Reference(s): JP 59 222 497 (Shionogi & Co.; appl. 1.6.1983). US 4 575 550 (Shionogi & Co.; J-prior. 11.3.1986; appl. 14.4.1983; J-prior. 23.10.1981; USA-prior. 6.1.1982). Totani, T.; Aono, K.; Komura, M.; Adachi, Y.: Chern. Lett. (CMLTAG) 1986 (3), 429. Trade Narne(s): J: Aqupla (S hionogi) Nedocromil ATC: R01 ACO7; R03BC03; SO 1 GXO4 Use: antiallergic, antiasthmatic RN: 69049-73-6 MF: Cl,H17N07 MW: 371.35 CN: 9-ethyl-6,9-dihydro-4,6-dioxo-1O-propyl-4H-pyrano[3,2-g]quinoline-2,8.dicarboxylic acid disodium salt RN: 69049-74-7 MF: C,,H,,NNa,O, MW: 41 5.31 LD,,: 2000-4000 mgkg (R, dog, i.v.); >5000 mglkg (R, dog, p.o., s.c.) 4-(acelylethylomino)- ally1 2-hydroxyacetophenone bromide 4-(acety1ethylamino)- 2-allyloxyocetophenone (I) OVOTH~ CH3 polyphorphoric acid U + b H3C.0 A H3C.0 iH3 C oAo-cH3 0 0 0 0 dimethyl acetylene- dimethyl [N-(4-acetyl- methyl 1 -ethyl-6-ocetyl-7- dicarboxylote 3-hydraxy-2-propylpheny1)- hydroxy-4-0x0-8-propyl- N-ethylomino]rnoleate W-quinoline-2-carboxylote (Dl) . 3-( 2-bromo- ocetylomino )-5 -chloro- salicylote 1408 N Nebivolol 6-chloro-3. 4- dihydro-4-methyl- 3-0 x 0-2 H-1.4-benz- oxazine- 8- carboxylic ocid (U) 6-chloro-3. 4- dihydro-4-methyl-. (Y-25 130) ATC: A04AA Use: anti-emetic, 5-HT3-antagonist RN: 12304 0-6 9-7 MF: C17H20CIN,03 MW. 349.82 CN: (~)-N-l-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine- 8-. 6-fluoro-4-oxo- 3. bis(2-rnethylpropyl )- 6-fluoro-3.4-dihydro- benzopyron- 2- olurninum hydride 2H-benzopyran- 2- carboxylic ocid carboxaldehyde (I) 6-fluoro-3.4-dihydro- 2-oxiranyl-2H- 1- benzopyran