Pharmaceutical Substances Syntheses, Patents, Applications - Part 15 docx

Aspoxicillin A 141 with immovable E. coli (ATCC 11303): Sato, T. et al.: Biotechnol. Bioeng. (BIBIAU) 17, 1797 (1975). US 3 791 926 (Tanabe; 12.2.1974; J prior. 28.10.1971). US 4 138 292 (Tanabe, 6.2.1979; J-prior. 2.7.1976). Fusee, M.C. et a].: Appl. Environ. Microbiol. (AEMIDF) 42,672 (1981). US 4 436 813 (Purification Engineering; 13.3.1984; appl. 16.3.1982). US 4 560 653 (Grace; 24.12.1985; appl. 6.6.1983). EP 110 422 (Tanabe; appl. 2.12.1983; J prior. 3.12.1982). Fonnulation(s): many different formulations Trade Name(s): D: Eubiol (Chephasaar) F: Megamag (Mayoly- numerous combination numerous combination Spindler; as magnesium preparations preparations salt) I: Oral K (Sc1avo)-comb. Sargenon (ASTA Medica; Polase (Wyeth)-comb. with arginine) Aspoxicillin (TA-058) ATC: JO1 Use: semisynthetic penicillin (for parenteral administration), derivative of amoxicillin RN: 63358-49-6 MF: C21H,N507S MW: 493.54 LD,,: >logkg (M, i.v.) CN: [2S-(2a,5a,6~)]-N-methyl-~-asparaginyl-N-(2-carboxy-3,3-dimethyl-7-oxo-4-thia- 1 - azabicyclo[3.2.0]hept-6-yl)-D-2-(4-hydroxyphenyl)glycinamide 0 NH, Nps-CI . K2CD3. pH 8 HN/N~s o-nitrophenyl- H3C\O~COOH sulfenyl chloride 4-methyl D-ospartate (1) hydrochloride I H ~ succinimide ~*-meth~l-~?- 142 A Aspoxicillin I OH amaxicillin (9. v.) 0-4-hydrony- phenylglycine thiobenzarnide OH (111) CO~H 3. N~H, , N(C2H5),, -25 OC Ls CH, HzN H 0 H Aspoxicillin Aspoxicillin r-7 2. isobutyl chloraforrnate 3. 6-arninopenicillanic acid 4. thiobenzarnide Reference(s): Wagatsuma, M. et al.: J. Antibiot. (JANTAJ) 36, 147 (1983). US 4 053 609 (Tanabe Seiyaku; ll.lO.1977; UK-prior. 12.9.1975; J-prior. 27.12.1975, 29.12.1975). GB 1 533 413 (Tanabe Seiyaku; appl. 12.9.1975 and 16.8.1976). GB 1 533 414 (Tanabe Seiyaku; appl. 3.12.1976; J-prior. 27.12.1975). DOS 2 638 067 (Tanabe Seiyaku; appl. 24.8.1976; GB-prior. 12.9.1975, 27.12.1975, 29.12.1975). puri'catinn: US 4 313 875 (Tanabe Seiyaku; 2.2.1982; J-prior. 11.9.1979). EP 25 233 (Tanabe Seiyaku; appl. 10.9.1980; J-prior. 11.9.1979). trihydrate: US 4 866 170 (Tanabe Seiyaku; 12.9.1989; J-prior. 24.9.1986). EP 261 823 (Tanabe Seiyaku; appl. 3.9.1987; J-prior. 24.9.1986) Astemizole A 143 lyophilized preparation: US 4 966 899 (Tanabe Seiyaku; 30.10.1990; J-prior. 14.1.1987). Formulation(s): powder in vial 1 g, 2 g Trade Name(s): J: Doyle (Tanabe; 1987) Astemizole (R 43512) ATC: R06AX11 Use: antihistaminic, antiallergic RN: 68844-77-9 MF: C,,H,,FN,O MW: 458.58 EINECS: 272-441-9 LD,,: 35 mag (M, i.v.); 2560 mglkg (M, p.0.); 28.2 mglkg (R, i.v.); >2560 mglkg (R, p.0.); 21.8 mglkg (dog, i.v.); >320 mglkg (dog, p.0.) CN: l-[(4-fluorophenyl)methyl]-N-[I-[2-(4-methoxyphenyl)dhyl]-4-piperidinyl]-1H-benzimidazol-2-amine H2N ~o~cH3 ethyl 4-ornino- piperidine-1 -carboxylaie 2-nitro- N,N-diethyl- 1 -isothiocyanato- aniline thiocarbomoyl 2-nitrobenzene chloride 4-fluorobenzyl chloride 0 2-(4-methoxyphenyl)- Asternizole 144 A Astromicin Reference (s): US 4 219 559 (Janssen; 26.8.1980; prior. 10.1.1979). EP 5 3 18 (Janssen; appl. 30.3.1979; USA-prior. 10.1.1979; 3.4.1978). synthesis of 1 -isothiocyanato-2-nitrobenzene: Sayigh, A.A.R.: J. Org. Chem. (JOCEAH) 30,2465 (1965). synthesis of N,N-diethylthiocarbamoyl chloride: Goerdeler, J.; Luedke, H.: Chem. Ber. (CHBEAM) 103,3393 (1970). v. Braun: Ber. Dtsch. Chem. Ges. (BDCGAS) 36,2274 (1903). Billeter: Ber. Dtsch. Chem. Ges. (BDCGAS) 26, 1686 (1893). Goshorn et al.: Org. Synth. (ORSYAT) 35,55 (1955). US 2 466 276 (Sharples Chemicals Inc.; 5.4.1949; appl. 2.2.1946). Formulation(s): drops 2 mglml; susp. 30 ml (0.2 %); tabl. 10 mg Trade Name(s): D: Hismanal (Janssen-Cilag; GB: Hismanal (Janssen-Cilag; J: Hismanal (Mochida) 1985) 1983) USA: Hismanal (Janssen) F: Hismanal (Janssen-Cilag; I: Hismanal (Janssen; 1987) 1986) Histamen (Polifarma) Astromicin (Fortimicin A) ATC: JOlG Use: aminoglycoside antibiotic RN: 55779-06-1 MF: C17H3,N506 MW: 405.50 LD,,: 380 mglkg (M, i.v.); 400 mglkg (M, p.0.) CN: 4-amino-l-[(aminoacetyl)methylamino]-1,4-dideoxy-3-0-(2,6-diamino-2,3,4,6,7-pentadeoxy-~-~-lyxo- heptopyranosy1)-6-0-methyl-L-chiro-inositol sulfate (1:2) RN: 72275-67-3 MF: C17H35N50h. 2H2O4S MW: 601.65 LD,,: 94mgkg(M,i.v.); 13.6g/kg(M,p.o.); 86 mgkg (R, i.v.); >10 gkg (R, p.0.); 214 mgkg (dog, i.v.) Astromicin Preparation by fermentation of Micromonospora olivoasterospora FERM-P1560 (identical with Micromonospora sp. MK-70; ATCC 31009 and ATCC 31010) and isolation/purification on ion-exchanger and column chromatography. Atenolol A 145 Reference(s): Nara, T. et al.: J. Antibiot. (JANTAJ) 30, 533 (1977). Okachi, R. et al.: J. Antibiot. (JANTAJ) 30, 541 (1977). US 3 976 768 (Abbott; 24.8.1976; appl. 22.7.1974; J prior. 23.7.1973). GB 1 473 356 (Abbott; appl. 22.7.1974; J prior. 23.7.1973). FR 2 238 502 (Kyowa Hakko; appl. 22.7.1974; J prior. 23.7.1973). DE 2 435 160 structure: Egan, R.S. et al.: J. Antibiot. (JANTAJ) 30,552 (1977). Formulation(s): amp. 200 mg Trade Narne(s): J: Fortirnicin (Kyowa Hakko; 1985) Atenolol ATC: C07AA; C07AB03 Use: antiadrenergic (P-receptor), antihypertensive RN: 29122-68-7 MF: CI,H22N203 MW: 266.34 EINECS: 249-451-7 LD,,: >57 rnglkg (M, i.v.); 2 glkg (M, p.0.); 77 rngkg (R, i.v.); 2 glkg (R, p.0.) CN: 4-[2-hydroxy-3-[(1-rnethylethyl)amino]propoxy]benzeneacetamide. HO NoCN.NaOH, DMF. 130 T 2 DL-4-hydroxy- phenylgiycine 4-hydroxy- 4-hydroxyphenyl benzyl cyanide acetornide (I) @ alternative synthesis of 4-hydroxyphenylacetarnide arnine epichloro- 4-(2.3-epoxyprop0xy)- HO HO aCOOH + H3C-OH - aq. NH, Atenolol 4-hydroxyphenyl- acetic acid hydrin phenylacetamide 146 A Atorvastatin calcium Reference(s): US 3 934 032 (ICI; 20.1.1976; prior. 10.3.1972). US 3 663 607 (ICI; 16.5.1972; GB-prior. 21.2.1969). US 3 836 671 (ICI; 17.9.1974; GB-prior. 21.2.1969, 24.9.1969, 18.11.1970 and 19.11.1970). DOS 2 007 75 1 (ICI; appl. 19.2.1970; GB-prior. 21.2.1969 and 24.9.1969), GB 1 285 038 (ICI; appl. 21.2.1969; valid from 24.9.1969). alternative synthesis: GB 1 391 444 (ICI; appl. 13.7.1971; valid from 19.6.1972). 4-hydroxybenzyl cyanide: GB 1 522 477 (ICI; appl. 13.8.1974; valid from 11.1 1.1975). US 4 154 757 (ICI; 15.5.1979; appl. 22.5.1978). Formulation(s): amp. 5 mg/lO ml; f. c. tabl. 25 mg, 50 mg, 100 mg Trade Name(s): D: Atebeta (betapharm) duratenol (durachemie) Falitonsin (ASTA Medica AWD) Tenormin (Zeneca; 1976) Tri-Normin (Zeneca; 1984) F: Betatop (EG Labo) Beta-Adalate (Bayer)- comb. Tenordate (Zeneca)-comb. TCnormine (Zeneca; 1979) GB: Beta-adalat (Bayer)-comb. Kalten (Zeneca)-comb. Tenben (Galen)-comb. Tenif (Zeneca)-comb. Tenoret-50 (Zeneca)-comb. Tenoretic (Zeneca)-comb. Tenormin (Zeneca; 1976) Totamol (CP Pharm.) J: Tenormin (ICI-Sumitomo Chem.; 1984) USA: Tenoretic (Zeneca; 1984) Tenormin (Zeneca; 1981) Atorvastatin calcium (CI-98 1; YM-548) ATC: ClOAA05 Use: hyperlipidemic, HMG-CoA- reductase inhibitor RN: 134523-03-8 MF: C,,H,,CaF,N40,, MW: 1155.36 CN: [R-(R*,R*)]-2-(4-fluorophenyl)-P,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl~- 1H-pyrrole-1-heptanoic acid calcium salt (2:l) free acid RN: 134523-00-5 MF: C,,H3,FN,0, MW: 558.65 (CH3 OH" "-a; CH3 F .HO ~~~7 + 6 - 3% THF, N(C2H5)3 b1 a"", 4-fluorabenzaldehyde. thiozoliurn salt \ 2-isobutyryl- benz- 2-benzylidene-4- ocetanilide oldehyde rnethyl-3-oxa-N- phenylpentanornide Atorvastatin calcium A 147 1. pivalic wid. toluene 2. HCI. CH30H - CHO 4-(4-f1uorophenyl)-2- 3-ominopropion. isabutytyl-3-phenyl- aldehyde 4-0x0-N-phenyl- diethyl ocetol butyrornide (I) 5-(4-fluoropheny1)-2-(1- methylethyl)-1 -(3-0x0- propyl)-N.4-diphenyl- 1H-pyrrole-3-corbox- omide (11) 1. MgBr?. THF, -80 "C 2. CH3COOH _______) (5)-(+)-2-ocetoxy- 1.1 ,2-triphenyl- ethanol BuLi. THF b v tert-butyl . ocetota 1. NoOH. THF. CH,OH 2. HCI 3. chrornatogrophy VI b 148 A Atorvastatin calcium 1. NaOH. CH30H, H20 2. CaCI?, H20 Atorvastatin calcium (R)-(+)-u- methyl- benzylamine 1. separation by HPLC or crystallization 2. NaOH 3. reflux, toluene VIII b Atorvostatin H3C CH, X 2. NaCN (X). OMS0 H C Cti, X CHO O O CH O O O - H&~0x,,,+131313 ,,,, CN H3C~O%,~~+'u~'%/0H 1. p-chlorophenyl- H3C sulfonyl chlaride H3C tert-butyl (4R,6S)-2- tert-butyl (4R.6R)-2- (6-hydraxyrnethyC2.2- (6-cyonomethyl-2.2-dimethyl- dimethyl-1 -3-diaxan- 1.3-dioxan-4-yl)acetate (XI) 4-yl)acetate I Atorvastatin calcium A 149 Hz, 50 psi, sponge Ni H C CH, XI - X CHO O O H3C~O~~~"'u"I/\N H2 H3C tert-butyl (4R.6R)-2- [6-(2-ominoethy1)-2.2- dimethyl-1,3-dioxon-4- yllocetate (XI) 1. pivolic ocid, toluene 2. HCI. CH30H, H20 xU+I -, YI + @ olternotive synthesis of interrnediote XI: ethyl 3(R)-hydroxy- 4-cyonobutyrote (XII1) tert-butyl 5(R)-hydroxy- 6-cyono-3-oxohexonoote (XW) 1. B(C2H5)3. NoBH,. -65 OC H C CH3 2. X ? ? H3C CH3 XIV , xl 1. triethylborone 2. ocetone dirnethyl acetol @ synthesis of the starting moterial XII: ethyl 4-bromo-3(S)- hydroxybutonoote @ olternotive synthesis of intermediote n: n OyO n ocetonitrile + ____, NH2 2-(1,3-dioxolon- ethyl 2-bromo- 2-yl)ethylomine 2-(4-fluorophenyl) ocetote ethyl 2-[2-(1.3-dioxolon- 2-yl)ethylamino]-2-(4- fluorophenyl)ocetote (XV) isobutyryl chloride 150 A Atracurium besilate N,3-diphenyl- propynomide 1 -[2-(1,3-dioxolan-2- yl)ethyl]-5-(4-fluoro- phenyl)-2-(1 -methyl- ethyl)-N,4-diphenyl- 1 H-pyrrole-3-corb- oxamide Reference(s): a,b US 4 681 893 (Warner-Lambert; appl. 21.7.1987; USA-prior. 30.5.1986). EP 409 281 (Warner-Lambert; appl. 23.1 .I991 ; USA-prior. 21.7.1989, 26.2.1991). EP 680 320 ( Warner-Lambert; appl. 8.1 1.1995; USA-prior. 19.1.1993). c Naeminga, T. et al.: Tetrahedron Lett. (TELEAY) 33, 2279-2282 (1992). WO 9 703 960 (Warner-Lambert; appl. 6.2.1997; USA-prior. 17.7.1995). ca Baumann, K.L. et al.: Tetrahedron Lett. (TELEAY) 33, 2283-2284 (1992). cb Isbell, H. et a].: Carbohydr. Res. (CRBRAT) 72,301-304 (1972). d Roth, B.D. et al.: J. Med. Chem. (JMCMAR) 34,357-366 (1991). preparation of N,3-diphenylpropynamide: Gadwhal, S. et al.: Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. (IJSBDB) 37B (8), 725-727 (1998). preparation of intermediates: WO 9 932 434 (Warner-Lambert; appl. 2.12.1998; USA-prior. 19.12.1997). WO 9 957 109 (Kaneka Corp.; appl. 28.4.1999; J-prior. 30.4.1998). WO 9 804 543 (Warner-Lambert; appl. 1.7.1997; USA-prior. 29.7.1996). US 5 155 25 1 (Warner-Lambert; appl. 13.10.1992; 11.10.199 1). US 5 103 024 (Warner-Lambert; prior. 17.10.1990). new crystalline forms of atorvastatin: WO 9 703 959 (Warner-Lambert; appl. 8.7.1996; USA-prior. 17.7.1995). WO 9 703 958 (Warner-Lambert; appl. 6.2.1997; USA-prior. 17.7.1995). stable oral formulation: WO 9 416 693 (Warner-Lambert; appl. 4.8.1994; USA-prior. 19.1.1993). Formulation(s): tabl. 10 mg, 20 mg, 40 mg Trade Name(s): D: Sotis (Parke Davis1 J: Lipitor (Warner-Lambert) Xavator (Parke Davis) Godecke; Mack, Illert.) Torvast (Pfizer) USA: Lipitor (Parke Davis; GB: Lipitor (Parke Davis) Tozalip (Guidotti) Pfizer) Atracurium besilate ATC: M03AC04 Use: skeletal muscle relaxant RN: 64228-81-5 MF: C53H,2N20,, . 2C6HsO3S MW: 1243.50 EINECS: 264-743-4 CN: 2,2'-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4- tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate . [2S-(2a,5a,6~)]-N-methyl-~-asparaginyl-N-(2-carboxy-3,3-dimethyl-7-oxo-4-thia- 1 - azabicyclo[3.2.0]hept-6-yl)-D- 2-( 4-hydroxyphenyl)glycinamide 0 NH, Nps-CI . K2CD3. pH 8 HN/N~s o-nitrophenyl-. - CHO 4-( 4-f1uorophenyl )-2 - 3-ominopropion. isabutytyl-3-phenyl- aldehyde 4-0 x0-N-phenyl- diethyl ocetol butyrornide (I) 5-( 4-fluoropheny1 )-2 -( 1- methylethyl )-1 -( 3-0 x 0- propyl)-N.4-diphenyl-. CN: l-[(4-fluorophenyl)methyl]-N-[I-[ 2-( 4-methoxyphenyl)dhyl ]-4 -piperidinyl ]-1 H-benzimidazol-2-amine H2N ~o~cH3 ethyl 4-ornino- piperidine-1 -carboxylaie 2-nitro- N,N-diethyl- 1 -isothiocyanato-