Quinapril hydrochloride Q 177 1 a,ypo + HOBt. THF. N(C,H,),. OCC, 3-5 OC H3CX~ 1 -hydroxybenzotriazole w '3' CH, (W I Quinapril hydrochloride 1. CF3COOH 2. NaOH 3. HCI v + Ul + HOa polyphosphoric acid 0 m&yebCH3 CH "'COOH HCI benzyl alcohol tetrahydro-3-isoquinoline- tarboxylate (VI) 3. HCI VI + I1 Quinopril hydrochloride 1. 1 -hydroxybenrotriarole, dicyclohexyicarbodiirnide Referencers): a EP 49 605 (Warncr-Lambert; appl. 1.10.1981; USA-prior. 20.2.1981, 3.10.1980). US 4 344 949 (Warner-Lambert; 17.8.1982; appl. 20.2.1981 ; prior. 3.10.1980). Klutchko, S. et d.: J. Med. Chem. (JMCMAR) 29, 1953 (1986). b EP 49 605 (Warner-Lambert; appl. l.lO.l98l; USA-prior. 20.2.198 1, 3.10.1980). US 4 344 949 (Warner-Lamhert; 17.8.1982; appl. 20.2.1981; prior. 3.10.\980). crystalline quinapril hydrochloride: EP 285 992 (Warner-Lambert; appl. 29.3.1988; USA-prior. 30.3.1987). US 4761 479 (Warner-Lambert; 2.8.1988; appl. 30.3.1987). preparation of ethyl 2-bromo-4-phenylbutanoate and 2-bromo-4-phenylbutanoic acid: Fischer, E.; Schmitz: Ber. Dtsch. Chem. Ges. (BDCGAS) 39, 2212 (1906). Baxter, A.D. et al.: Bioorg. Med. Chem. Lett. (BMCLE8) 7 (21), 2765 (1997). Iwasaki, G.; Kimura, R.; Numao, N.; Kondo, K.: Chem. Pharm. Bull. (CPBTAL) 37 (2), 280 (1989). Cork, P. et al.: J. Med. Chem. (JMCMAR) 39 (6), 1210 (1996). Goel, O.P.; Krolls, K.: Tetrahedron Lett. (TELEAY) 24 (2), 163 (1983). stabilization of pharmaceutical formulations: EP 264 887 (Warner-Lambert; appl. 19.10.1987; USA-prior. 20.10.1986). EP 264 888 (Warner-Lambert; 19.10.1987; USA-prior. 20.1 0.1986). EP 280 999 (Warner-Lambert; appl. 23.2.1988; USA-prior. 24.2.1987). Formulation(s): f. c. tabl. 5 mg, 10 mg, 20 mg, 40 mg 1772 Q Quinestrol Trade Narnefs): D: Accupro (Godeckemarke Korec (Sanofi Winthrop) Quinazil (Malesci; 1989) Davis; 1991) Koretic (Sanofi Winthrop)- J: Conan (Yoshitomi-Green Accuzide (Godecke; Parke comb. Cross) Davis)-comb. GB: Accupro (Parke Davis) USA: Accupd (Parke Davis; F: Acuilix (Parke Davis)- I: Accuprin (Parke Davis; 1991) comb. 1989) Acuitel (Parke Davis; 1990) Acequin (Recordati; 1989) Quinestrol ATC: GO3 Use: estrogen RN: 152-43-2 MF: C,,H,,O, MW: 364.53 EINECS: 205-803-1 CN: (17a)-3-(cyclopentyloxy)- 19-norpregna- 1,3,5(10)-trien-20-yn-17-01 estrone cyclopentyl estrone 3-cyclopentyl (9. v.) bromide (1) ether (11) KOC(CH& + HCrCH potassium tert-butylate Reference(s): US 3 159 543 (F. Vismara S.V.A.; 1.12.1964; I-prior. 7.4.1961). CH acetylene DAS 1 157 610 (F. Vismara s.~.A.; appl. 7.2.1961; I-prior. 8.2.1960, 13.12.1960). Ercoli, A.; Gardi, R.: Chem. Ind. (London) (CHINAG) 1961, 1037. Ouinestrol alternative syntheses: US 3 231 567 (F. Vismara; 25.1.1966; I-prior. 16.12.1963). BE 641 351 (F. Vismara; appl. 16.12.1963; I-prior. 19.12.1962, 30.9.1963). Formulation(s): tabl. 0.025 mg, 0.1 mg Quinethazone Q 1773 Trade Name(s): D: Estrovis (Godecke); wfm Estrovis (Warner); wfm USA: Estrovis (Warner Chilcott); GB: Estrovis (Parke Davis); I: Colpovis (SIT) wfm wfrn Quinethazone (Chinethazonum) ATC: C03BA02 Use: diuretic, antihypertensive RN: 73-49-4 MF: CIOH,,ClN3O3S MW: 289.74 EINECS: 200-801-7 LDSo: >10 g/kg (M, p.0.) CN: 7-chloro-2-ethyl- 1,2,3,4-tetrahydro-4-oxo-6-quinazolinesulfonamide CI POCI, I CI phosphoryl chloride 5-ominosulfonyl- propionyl 4-chloroonthronil- chloride omide Reference(s): US 2 976 289 (American Cyanamid; 21.3.1961; prior. 30.6.1959). m3, Noen, aluminum sodium chloride borohydride 6-ominosulfonyl-7- Formulation(sl: tabl. 50 mg Puinethozons Trade Name(s): D: Aquamox (Lederle); wfm 1: Aquamox (Cyanamid); 1: , Hydromox (Lederle) GB: Aquamox (Lederle); wfm wfm USA: Hydromox (Lederle); wfm Ipotex (Cyanamid); wfrn Quingestanol acetate ATC: G03AC04 Use: progestogen RN: 3000-39-3 MF: C,H3,03 MW: 408.58 EINECS: 221-078-4 CN: (17a)-3-(cyclopenty1oxy)- 19-norpregna-3,s-dien-20-y n- 17-01 acetate quingestanoI RN: 10592-65-1 MF: C2,H3,02 MW: 366.55 EINECS: 234-199-2 1774 Q Quinidine kH 2. aOH, pyridine CH, , 2. cyclopentanol (I) norethisterane (4. Y.) Ouingestanol acetate Reference(s): a DE 1 159 940 (F. Vismara; appl. 1961 ; I-prior. 1961). addition to DE 1 119 264 (F. Visrnara; appl. 1959). b DE I 228 608 (F. Vismara; appl. 1.6.1964; I-prior. 12.6.1963). additlon to DE 1 119 264 (F. Vismara; appl. 1959). alternative synthesis: US 3 159 620 (E Vismara; 1 .l2.l964; I-prior. 22.5.1963). Trade Name(s): F: Dklovis (Substantia); wfm I: Demovis (Vister); wfm Quinidine ATC: COlBAOl Use: antiarrhythmic RN: 56-54-2 MF: C2,,Hz4N202 MW: 324.42 EINECS: 200-279-0 LD,,, 53.6mglkg(M,i.v.); 535mg/kg(M, p.0.); 23 mgkg (R, i.v.); 263 mg/kg (R, p.0.) CN: (9s)-6'-methoxycinchonan-9-01 I sulfate (21) RN 50-54-4 MF: C2,HZ4N2O2. 112H2S04 MW: 746.93 EINECS: 200-046-3 LD,,,: 54 mag (M, i.v.); 505 mglkg (M, p.0.); 55 mgkg (R, i.v.); 456 mgPag (R, p.0.) gluconate RN: 7054-25-3 MF: C,,H,N,O,. C,H,,O, MW: 520.58 EINECS: 230-333-9 polygalacturonate RN: 58829-32-6 MF: CzoHz4N2O2 . x unspecified MW: unspecified Quinine Q 1775 1. benzophenone, toluene 2. NoOCH3, isoproponal 3. H2S0, 4. NoOH 5. fractional crvstollization H quinine I Quinidine @ from the mother liquorr of the quinine production Reference(s): a DE 877 61 1 (Boehringer Mannh.; appl. 1950). b Ullmanns Encykl. Tech. Chem., 3. Aufl., Vol. 3, 212. polygalacturonate: US 2 878 252 (Synergistics; 1959; appl. 1957). quinidine alginate: DOS 2 156 725 (Lab. G A. Cochard; appl. 16.1 1.1971; B-prior. 19.1 1.1970, 8.1 1.1971). Formulation(s): f. c. tabl. 250 mg; s. r. tabl. 200 mg, 250 mg (as hydrogen sulfate); tabl. 166 mg, 275 mg (as polygalacturonate); s. r. tabl. 300 mg; tabl. 100 mg, 200 mg, 300 mg (as sulfate) Trade Namc(s): D: Chinidin Duriles (Astra) Chinidin-retard (Isis Pharma) Chinidinum Compretten (Cascan); wfm Chinidinum sulfuricum "Buchler" (Buchler); wfm Galactoquin (Mundipharma; as. polygalacturonate); wfm Optochinidin (Boehringer Mannh.; as hydrogen sulfate) Quinitex Extentabs (Brenner); wfm Systodin "Buchler" (Buchler); wfm numerous combination preparations F: Cardioquine (ASTA Medica; as polygalacturonate) Longacor (Procter & Gamble; as arabogalacturonate) Quinidurule (Astra) Quinimax (Sanofi Winthrop)-comb. GB: Kinidin Durules (Astra; as bisulfate) I: Chin el (Fadem) Chinina cloridrato (Biologici Italia) Chinina solfato (Iema) Chinteina (Lafare; as sulfate) Longachin (Teofarma) Naticardina (ASTA Medica) Natisedina (Teofarma) Nicoprive (IF1)-comb. Ritmocor (Malesci; as polygalacturonate) numerous generics J: Quinidine HCI (Nikken) Quinidine Sulfate (Alps; Hoei; Iwaki; Sanko; Yamada) generics USA: Cardioquin (Purdue Frederick; as polygalacturonate) Quinaglute Dura-Tabs' (Berex; as gluconate) Quinidex Extentabs (Robins; as sulfate) generics Quinine ATC: POlBCOl Use: chemotherapeutic, antipyretic, stimulant RN: 130-95-0 MF: C20H24N20, MW: 324.42 EINECS: 205-003-2 LD,,: 68 mgkg (M, i.v.) CN: (8a,9R)-6'-methoxycinchonan-9-ol 1776 Q Quinine hydrochloride RN: 7549-43- 1 MF: C2,H,,N202 . xHCI MW: unspecified EINECS: 23 1-437-7 sulfate (1:l) RN: 549-56-4 MF: C20H24N202. H2S04 MW: 422.50 EINECS: 208-970-9 iodobismutate RN: 8048-94-0 MF: C20H24N202. Bi13 . HI MW: 1042.03 acetylsalicylate (1: 1) RN: 130-93-8 MF: C20H24N202 . C9H804 MW: 504.58 monoformate RN: 130-90-5 MF: C20HxN202~ CH202 MW: 370.45 EINECS: 205-002-7 LDSo: 290 mg/kg (dog, i.m.) By extraction of Cinchona bark with aromatic hydrocarbons, conversion of the crude alkaloids into the sulfates and fractional precipitation with NaOH as sulfate. Reference(s): Ullmanns Encykl. Tech. Chem., 3. Aufl., Vol. 3,213. Ullmanns Encykl. Tech. Chem., 4. Aufl., Vol. 7,86. BIOS Final Reports No. 1404, p. 20. FR 1 279 901 (Omnium Chimique; appl. 1955). combination of quinine sulfate with theophylline ethylenediamine: US 2 985 558 (W. B. Rawls; 23.5.1961; appl. 27.2.1959). Formulation(s): amp. 245 mglml, 250 mg/ml (as dihydrochloride); tabl. 200 mg (as ethyl carbonate); tabl. 250 mg (as hydrochloride); tabl. 200 mg (as sulfate) Trade Namefs): D: Chininum aethylcarbonicum (Cassella-med) Chininum dihydrochloricum (Cassella-med) Chininum hydrochloricum (Merck) Chininum hydrochloricum Compretten (Cascan); wfm Chininum sulfuricum "Buchler" (Buchler); wfm Limptar (Cassella-med; as sulfate) Sagittaproct (BASF Generics) numerous combination preparations and generics F: Cequinyl (SmithKline Beecham)-comb. Dinacode (Picot)-comb. Hexaquine (Gomeno])- comb. KinurCa "H" (Fuca) Nicoprive (Thtranol- Deg1aude)-comb. Quinimax (Sanofi Winthrop)-comb. Quinine Lafran (Lafran; as hydrochloride) numerous combination preparations GB: numerous combination preparations; wfm I: Broncopulmin (Ecobi)- comb. Nicoprive (1FI)-comb. J: Quinine HCl (Alps; Hoei; Iwaki; Kotani; Sank; Takeda; Toni; Toyo S Ono; Yamada) Quinine Sulfate (Alps; Hoei; Iwaki; Sanko; Yamada) generics USA: Quinine Sulfate (Watson) Quinisocaine Q 1777 Quinisocaine (Dimethisoquin) ATC: D04AB05 Use: local anesthetic RN: 86-80-6 MF: C,,HXN2O MW: 272.39 EINECS: 201-700-0 LD,,,: 8 mglkg (M, i.v.) CN: 2-[(3-butyl-l-isoquinolinyl)oxy]-N,N-dimethylethanamine monohydrochloride RN: 2773-92-4 MF: Cl,H2,N20 . HCl MW: 308.85 EINECS: 220-468-1 LD,,: 45 mgkg (R, i.p.) 1. No, xylene FH3 0 Ci 2. FH3 &cH3 % aCH3 2. 2-dimethyl- 3-butyl-1-0x0-1,2- arninoethanol 3-butyl-1 -chloro- Ouinisocaine dihydroisoquinoline isoquinoline Reference(s): US 2 612 503 (Smith Kline & French; 1952; CDN-prior. 1949). Formulation(s): ointment 0.5 g1100 g (as hydrochloride) Trade Name(s): D: Haenal Salbe (Strathmann) Pruralgan Salbe GB: Quotane (Smith Kline & Isochinol (Schwarzhaupt) (Pharmacia) French); wfm lsochinol Salbe F: Quotane (Evans Medical) I: Pruralgin Pharmacia (Chemipharm) Rectoquotane (Evans (Importex); wfm Medical)-comb. Quinupramine ATC: N06AA23 Use: antidepressant RN: 31721-17-2 MF: C2,H2,N2 MW: 304.44 EINECS: 250-780-3 CN: 5-(l-azabicyclo[2.2.2]oct-3-yl)-10,11-dihydro-5H-dibenz[bflazepine NaNH2 , toluene b H sodium amide N + 3 10.1 1-dihydro-5H- S-phenylsulfonyl- dibenz[b,f]azepine oxyquinuclidine Quinupramine DOS 2 030 492 (Sogeras; appl. 20.6.1970; GB-prior. 20.6.1969). GB 1 252 320 (Sogeras; valid from 29.5.1970; prior. 20.6.1969). Formulation(s): vial 2.5 mg; tabl. 2.5 mg, 7.5 mg Trade Name(s): F: Kinupril (Bellon) 1778 R Rabeprazole sodium Rabeprazole sodium ATC: A02BC04 Use: gastric antisecretory, H+/K+-ATPase inhibitor RN. 1 17976-90-6 MF: C,,H,,N,NaO,S MW: 381.43 CN: (+)-2-[[[4-(3-Mcthoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulnyl]- lH-benz~midazole sodium salt acid RN: 117976-89-3 MF. C,,H21N,0,S MW: 359.45 H202, CHSCOOH conc. iiN03. CH conc. HZSO,. or OJ. HZ02 95°C N~cH3 b 0\Np3 b 'KN3H3 ' \ NO2 2.3-dimethyl pyridine 2.3-dimethyl- 4-nitropyridine N-oxide (I) conc. HCI. HO-O/CH3 1 70°C CH3 NOH. DMSO CH3 1 b 0~N&cH3 - 0\N2H3 CI 3-methoxy-l -propano1 0~0,~CH3 4-chloro-2.3- dimethylpyridine N-oxide 4-(3-methoxypropoxy)- 2.3-dimethypyridine N-oxide (D) 1. MCPBA Robeprorole sodium L- Racefemine R 1779 Reference(s): EP 268 956 (Eisai Co.; J-prior. 13.1 1.1986; 2.2.1987; 31.3.1987). WO 8 910 927 (Eisai Co.; appl. 11.5.1989; J-prior. 12.5.1988). preparation of 4-chloro-2,3-dimethylpyridine N-oxide: Kuehler, T.C.; Fryklund, J.; Bergman, H.A.; Weilitz, J.; Lee, A.; Larsson, H.: J. Med. Chem. (JMCMAR) 38 (25), 4906 (1995). pharmaceutical preprations: WO 9 953 918 (Eisai Co.; appl. 20.4.1999; J-prior. 20.4.1998). EP585 722 (Eisai Co.; appl. 17.8.1993; J-prior. 21.8.1992). WO 9 902 521 (Eisai Co.; appl. 10.7.1998; J-prior. 11.7.1997). Formulation(s): tabl. 10 mg, 20 mg (as sodium salt) Trade Name(s): D: Pariet (Eisai; Janssen- 1: Pariet (Eisai; 1998) Cilag; 1998) USA: Aciphex (Eisai) Racefemine ATC: A03 Use: antispasmodic, coronary vasodilator RN: 22232-57-1 MF: C,&NO MW: 269.39 EINECS: 244-856-5 CN: (R*,R*)-(+_)-a-methyl-N-(l-methyl-2-phenoxyethyl)benzeneethanamine hydrogen fumarate (1:l) RN: 1590-35-8 MF: C18H23N0 .C4H404 MW: 385.46 EINECS: 216-462-3 (?)-amphetamine phenoxyocetone I Rocefernine I Reference(s): NL-appl. 6 407 309 (Clin-Byla; appl. 26.6.1964; F-prior. 28.6.1963). Formulation(s): tabl. 50 mg; vial 50 mg/5 ml Trade Name(s): F: Dysmalgine (Clin-Comar- Dysmalgine (Clin-Midy); Byla); wfm wfm Raloxifene hydrochloride (LY-156758; Keoxifene) ATC: G03XCO1 Use: antiestrogen, prevention of osteoporosis RN: 82640-04-8 MF: CZ8H2,NO4S . HCI MW: 51 0.05 CN: [6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(l-piperidinyl)ethoxy]phenyl]methanone hydrochloride 1780 R Raloxifene hydrochloride 1. KOH, ethanol H3C-'00SH + mOICH3 2.ppA, loooC , H3C,0-dcH3 Br - 2. polyphosphoric - 3-mercapto- 4-rneihoxyphenacyl- acid onisole bromide 6-meihoxy-2-(4-rnethoxy- phenyl)benzo[b]thiophene (I) 220°C pyridine. DMAP pyridine rnesyl chloride AICI,, Ci 1.2-dichloroeihone ____, OrvN 3 4-[2-(1 -piperidinyl)- ethoxylbenzoyl chloride (111) 16-[(methylsulfonyl)oxy]-2-[4- (methylsulfonyi)oxy]phenyl]- benzo[b]ihien-3-yl][4-[Z-(1- piperidinyl)ethoxy]phenyl]- methonone hydrochloride (N) I Raloxifene hydrochloride 1. NaOH, ethanol 2. HCI _____, @ starting material 111 can be synthesized from HO~oH - HCI obN 3 1. K,CO,, DMF methyl 4-hydroxy- N-(2-chloro- benzoate (V) ethy1)piperidine 2. NaOH 3. Socl2 + ObOH 1. piperidine ethylene carbonate . 300 0-3 9-3 MF: C,H3,03 MW: 408.58 EINECS: 22 1-0 7 8-4 CN: (17a )-3 -( cyclopenty1oxy )- 19-norpregna-3,s-dien-20-y n- 1 7-0 1 acetate quingestanoI RN: 1059 2-6 5-1 MF: C2,H3,02 MW: 366.55 EINECS: 23 4-1 9 9-2 . estrogen RN: 15 2-4 3-2 MF: C,,H,,O, MW: 364.53 EINECS: 20 5-8 0 3-1 CN: (17a )-3 -( cyclopentyloxy )- 19-norpregna- 1,3,5(10)-trien-20-yn-1 7-0 1 estrone cyclopentyl estrone 3-cyclopentyl (9 Ci 1.2-dichloroeihone ____, OrvN 3 4-[ 2-( 1 -piperidinyl )- ethoxylbenzoyl chloride (111) 1 6-[ (methylsulfonyl)oxy ]-2 -[ 4- (methylsulfonyi)oxy]phenyl ]- benzo[b]ihien-3-yl][ 4-[ Z-( 1- piperidinyl)ethoxy]phenyl]-