Pharmaceutical Substances Syntheses, Patents, Applications - Part 70 doc

Docetaxel D 691 Troc, Troc-CI CH3 - MH HW'' pyridine, CI-~I OH *oH~yc~3 + 10-deacetylbaccatin UI (oxtmctsd and purified from leaves of Taxus baccato L.) (1) Troc: h'0wCC13 0 ,Troc DCC. DMAP. toluene Boc\ 4-dimethylomino- pyridine oxy)-3-(tert-butoxy- corbonylomino)-3- phenylpropionic acid (11) Zn. CH,COOH, ethyl acetate ___f I Docetaxel @ synthesis of intermediate Il - 2. HCI, C2H,0H 3. Hz. Pd-C. C,H,OH 0 tort-butyl 3-phenylglycidate 0 H ethyl threo-3-amino- 2-hydroxy-3-phenyl- propionote (N) 692 D Docetaxel 2. H~C+O"CH~ , CH~CI~, H+ 3. LiOH. CZH50H N b n 1. di-tert-butyl dicarbonate 2. vinyl ethyl ether DCC. DMAP. toluene cinnamic acid ('w CI Boc-N- No+ OsO,. CHSCN VI- sodium tert-butyl Trot., Zn, CH3COOH e- (electrochem. reduction), CH3COOH. NaOAc. CHSOH 111 b Docetoxel El N(C2H5)31 ether, OCH0 dibutylborotriflate -, VII benz- aldehyde OH 0 0 H~C-L~ U'-xY0 hexane, THF ___, 3 Q ("I0 ethyl (2R.3R)-3- phenyl-2-oxirane- carboxylate (VIII) Docetaxel D 693 1. NaNE psOH 2. Hz, Pd-C.ethyl acetate 3.V. CHzC12 b Boc H OH ethyl (2R,SS)-3-tert-butaxy- corbonylomino-2-hydroxy- 3-phenylpropionate (IX) 1. TosOH, pyridine, toluene P/CH3 2. LDH, C2H@H .COOH t b Z-methoxy- propene (4S,5R)-3-tert-butoxy- corbonyl-2.2-dimethyl- .4-phenyl-5-oxozolidine- corboxylic acid (X) Troc, ,Troc DCC. DMAP, toluene Zn, CH3COOH Docetoxel oltemative synthesis of intermediate X 1. DIBAL, toluene tetrobutyl ammonium fluoride xn b 1. dibutylaluminum hydride 2. 2-(trimethylsilyl)thiozole Boc, H OH tert-butyl (lS.2R)-2-hy- droxy-1 -phenyl-2-(2-thio- zolyl)ethylcorbomote (XUl) 694 D Docetaxel 1. H3C 0 )( 0- CH3 , CSA H3C CH, 2. F3C-SO2-0-CH3 xm Boc, 1. 2.2-dimethoxypropane. 10-compharaulfonic acid H~C+O 2. methyl trifluoro- '3'3 methonesulfonote (4S,5R)-3-tert-butoxy- corbonyl-2.2-dimethyl-4- phenyl-5-oxozolidine- corboxaldehyde (XIV) KMnO.,, tert-butanol XIV .x 2-ocetoxy- ocetyl chloride 1. KOH. THF 2. HCI, C2H50H XV _____* ethyl (2RJS)-2-hydroxy- 3-[(S)-1 -phenylethylamino]- 3-phenylpropionate ethyl (2R.X)-3-omino- 2-hydroxy-3-phenyl- propionate (XVI) Boc, Q + N CHO H Boc-(S)- phenylqlycinol vinylmagnesium bromide I - Docetoxel , I CH3 3-ocetoxy-4-phenyl- 1- [(S)-1-phenylethyll-2- ' ozetidinone (XV) (?)-1 -phenyl-1- (tert-butoxycorbonyl- amino)-2-hydroxy- 3-butene (XVII) P Docetaxel D 695 molecular sieve XVII + Br,0,CC13 CH2 H 0,0,CC13 ethoxy)rnethyl bromide 1. RuCI,. CH3CN 2. (+)-ephedrine, ocetone 0,O,CCI3 (2RJS)-3-tert-butoxy- carbonylornino-3-phenyl- 2-(2,2,2-trichloroethoxy- rnethoxy)propionic acid (XIX) 1. DCC, DMAP, toluene 2. Zn. CH3COOH. CH30H mt1 H H3CyNyCH3 . THF CH3CH3 H~C-L~ . 0 OC . diisopropylarnine N-(ttirnethyl- 9ilyl)benz- aldehyde irnine H3C CH3 1. N+Bu4F-, THF H3C Y CH, 2. H~c-"o*cH~. o oc b~i4 3. v , CH,CI,, DMAP p3 H3c O.,,,,,,, - cH3+''0 I. tetrabutylarnrnoniurn '-' fluoride 0 2. ethyl vinyl ether (3R,4S)-3-(triisopropyl silyloxy)-4-phenyl-2- azetidinone (XX) 1. NaH, /0+~/~~3 , - 10 OC 2. HCI H3C I o b~, BOC (3R,4S)- 1 -tert-butoxy- corbonyl-3-(1 -ethoxy- ethoxy)-4-phenyl-2- azetidinone (XXI) 3. Zn, CH3COOH. CH30H )(X1 +I 696 D Docetaxel 1. KoY'H, . THF CH, 0 I1 2. H3C-S-CI . THF II 0 I1 b N-0 (4S.5R)-2-tert-butoxy-4-phenyl- 5-(1 -ethoxyethoxy)-4,5-dihydro- 1.3-oxazin-&one (XXII) XXII ti3CWLi THF ____* Reference(s): a EP 336 841 (RhBne-Poulenc Sante; appl. 5.4.1989, F-prior. 6.4.1988). Gueritte-Vocgelein, F. et al.: J. Med. Chem (JMCMAR) 34, 992-998 (1992). EP 522 958 (RhBne-Poulenc Rorer; appl. 8.7.1992; F-prior. 10.7.1991). Denis, J.N. et al.: J. Org. Chem. (JOCEAH) 51,46-50 (1986). 1 b EP 253 738 (RhBne-Poulenc Sante; appl. 16.7.1987; F-prior. 17.7.1986). $ c WO 9 3 18 210 (RhBne-Poulenc Rorer; appl. 11.3.1993; F-prior. 13.3.1992). k d WO 9 209 589 (RhBne-Poulenc Rorer; appl. 22.11.199 1; F-prior. 23.1 1.1990,25.7.1991). WO 9 407 879 (RhBne-Poulenc Rorer; appl. 4.10.1993; F-prior. 5.10.1992). WO 9 410 169 (RhBne-Poulenc Rorer; appl. 28.10.1993; F-prior. 30.10.1992). WO 9 407 876 (RhBne-Poulenc Rorer; appl. 4.10.1993; F-pr~or. 5.10.1992). "8 Dondoen, A. el al Synthesis (SYNTBF) 2, 181 (1995) j) e WO9 317 997 (RhBne-Poulenc Rorer; appl. 8.3.1993; F-pr~or. 10.3.1992). % WO 9 407 847 (RhBne-Poulenc Rorer; appl. 4.10.1993; F-pnor. 5.10.1992). ; f EP528 729 (RhBne-Poulenc Rorcr; appl. 17.8.1992; F-prior 19 8 1991). g W0 9 418 164 (Res. Found. SUNY; appl. 28.1.1994; USA-prior. 1.2.1993). W09 306 094 (Univ. Florida State; appl. 22.9.1992; USA-prior. 3.4.1992, 23.9.1991). 1. h US 5 254 703 (Unw. Florida State; appl. 6.4.1992; USA-prior. 6.4 1992) I, punjication of 10-deacetylbaccatin 111 by partition chromatography: ; W0 9 421 622 (RhBne-Poulenc Rorer; appl. 18.3.1994; F-prior. 22.3.1993). i '* callus cell induction and the preparation of taxanes: [ EP568 821 (Squibb; appl. 6.4.1993; USA-prior. 7.4.1992). 1 pur~jication of (2R,3R)-cis-P-phenylglycidic acid by crystallization with a-rnethylbenzylamine: [- WO 9 113 066 (RhBne-Poulenc Rorer; appl. 20.2.1991; F-prior. 21.2.1990). total synthesis of taxanes: I Nicolaou, K.C. et a].: Angcw. Chem. (ANCEAD) 107,2247-2259 (1995). 1 composition comprising taxanes in solution with ethanol, EP 522 936 (RhBne-Poulenc Rorer; appl. 3.7.1992; F-prior. 8.7.1991). composition with phospholipids/su~actants: WO 9 528 923 (RhBne-Poulenc Rorer; appl. 24.4.1995; F-prior. 25.4.1994). US 5 415 869 (Res. Found. SUNY; appl. 12.1 1.1993; USA-prior. 12.11.1993) WO9 412 171 (Rh8ne-Poulenc Rorer; appl. 26.1 1.1993; F-prior. 2.12.1992). " formulations with cyclodextrin: WO 9 519 994 (CNRS; appl. 24.1.1995; F-prior. 25.1.1994). combinations with antineoplastic agents: FR 2 697 752 (RhBne-Poulenc Rorer; appl. 10.11.1992; F-prior. 10.1 1.1992). we to treat malaria: FR 2707 165 (RhBnc-Poulenc Rorer; appl 6.7.1993; F-prior. 6.7.1993). WO 9 412 172 (Th. Jefferson Univ.; appl. 2.12.1993; USA-prior. 2.12.1992, 26.1.1993). Fomulation(s): vial 20 mg, 80 mg Trade Name(s): D: Taxotere mhBne-Poulcnc GB: Taxotere (RhBne-Poulenc USA: Taxotere (RhBne-Poulenc Rorer) Rorer) Rorer) F: Taxotkre (Bellon) J: Taxotere (RhBne-Poulenc Rorer) 698 D Dodeclonium bromide Dodeclonium bromide ATC: D08AJ Use: antiseptic RN: 15687- 13-5 MF: C,2H3,BrCIN0 MW: 448.92 EINECS: 239-779-9 CN: N-[2-(4-chlorophenoxy)ethyl]-N,N-dimethyl-l-dodecanaminium bromide 4-chlorophenol 1,2-dibromo- ethane Reference(s): Gautier, J.A. et al.: Bull. Soc. Chim. Fr. (BSCFAS) 1957, 1014. Gautier, J.A. et al.: C. R. Hebd. Seances Acad. Sci. (COREAF) 240,2154 (1955). H3C,N'(CH2) 11 -CH3 I + 1 + CH3 dodecyldimethylamine germicidal aerosol combination: FR 2 616 065 (J. Y. Pabst; appl. 2-6-1987). CI )Qo'3&$(cH2), iPcn3 CH3 B r- Dodeclonium bromide Formulation(s): cream 100 gl0.4 g; suppos. 1.3 mg Trade Narne(s): F: DermCol (RPR Cooper)- Sedorrhoide (RPR comb. Cooper)-comb. Dofetilide (UK-68798) Use: class I11 antiarrhythmic agent RN: 1 15256-1 1-6 MF: C,,H,,N,O,S, MW: 441.57 CN: N-[4-[2-[Methy1[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]methanesulfonamide 2. HJC-I , THF, NOH 3. NaOH, H20, CH30H rNH2 . ______, O2N 1. trifluoroacetic anhydride O2N rNH 2. methyl iodide 4-nitrophenethylomine N-methyl-2-(4-nitro- hydrochloride phenyl)ethylomine (1) Dofetilide D 699 I 2-chloroethyl i i 4-n~trophenyl ether (11) (prepared as in f method @ ) 1. H,, Roney-Ni. C2H50H I "m 2 rnethanesulfonic anhydnde (N) Dafetilide sodium 4-nitro- 1.2-dichloro- i phenolate ethane i I 1. HZ, Pd-C or Fe, HCI I 2 IV. CH&I2 //O I, K2C03. KI, CH3CN ; I1 + CkPo 0 i H N, $I 1. Hz. Raney-Ni, C2H50H 7H3 I 2 IV CH2CIz 4 2s\CH, Dofetilide C 02N \ (V) : Reference(s): EP 245 997 (Pfizer; appl. 29.4.1987; GB-prior. 1.5.1986). Cross, P.E.; Arrowsm~th, J.E.; Geoffrey, N.; Gwilt, M.; Burges, R.A. ; Higgins, A.J.: J. Med. Chem. (JMCMAR) 33,1151 (1990). j dofetilide polymorphs: 1 WO 9 921 829 (Pfizer; appl. 9. 10.1998; GB-prior. 27.10.1997) I I alternative preparation of N-methyl-(4-nitrophenethy1)amine: Dale, W.J.; Buell, C.J.: J. Org. Chem. (JOCEAH) 21, 45 (1956). Theodore, L.J.; Nelson, W.L.; Dave, B.; Giacomini, J.: J. Med. Chem. (JMCMAR) 33 (2), 873 (1990). alternadve preparation of 2-chloroethyl4-nitrophenyl ether: Katrak: J. Indian. Chem. Soc. (JICSAH) 13, 334 (1936). McMahon, R.E. et al.: J. Mcd. Chem. (JMCMAR) 6,343 (1963). US 3 937 726 (Hoechst A. G.; 10.2.1976; D-prior. 22.4.1966). 700 D Dolasetron mesilate Trade Name(s): D: Tikosyn (Pfizer; 2000) GB: Tikosyn (Pfizer; 2000) USA: Tikosyn(Pfizer; 1999) Dolasetron mesilate (MDL-73 147EF) ATC: A04AA04 Use: antiemetic agent (5-HT,-receptor antagonist) RN: 1 15956-13-3 MF: C,yH20N203 . CH403S MW: 420.49 CN: (2a,6a,8a,9aa)-lH-Indole-3-carboxylic acid octahydro-3-oxo-2,6-methano-2H-quinolizin-8-y1 ester base RN: 115956-12-2 MF: C,yH20N203 . CH4O3S MW: 420.49 cis-1,4- diethyl dichloro- malonote 2-butene (I) diethyl 3- cyclopentene- 1.1 -dicorboxylate (II) 1. KOH. C2H@H 1. S0Cl2 2. conc. HCI. A I1 , J-cyclopentene- 1 -corboxylic ocid Q . .so4 (cot.). H,C 0 Na104. H20, acetone H,O, THF 7 N-methylmorpholine HO sodium N-oxide. CH3 periodote ethyl 3-cyc10- osmium tetroxide diostereorneric pentene-l- carboxylate (IIl) p-ethoxycorbanyl- glutaraldehyde (N) mixture of 4- ethoxycorbonyl- 1.2-cyclopentanediol 1. ocetonedicorboxylic acid ?'kEffrCH3 2. glycine ethyl ester hydrochloride 3. potassium hydrogen phtholate 7-ethoxycarbonyl-9- (ethoxycorbonylmethyI)- 9-arabicyclo[3.3.l]nonon- 3-one (V) . (2R.X )-3 -omino- 2-hydroxy-3-phenyl- propionate (XVI) Boc, Q + N CHO H Boc-(S )- phenylqlycinol vinylmagnesium bromide I - Docetoxel , I CH3 3-ocetoxy-4-phenyl- 1- [(S )-1 -phenylethyll- 2-. agent (5-HT,-receptor antagonist) RN: 1 1595 6-1 3-3 MF: C,yH20N203 . CH403S MW: 420.49 CN: (2a,6a,8a,9aa)-lH-Indole-3-carboxylic acid octahydro-3-oxo-2,6-methano-2H-quinolizin-8-y1 ester. (3R,4S )- 1 -tert-butoxy- corbonyl- 3-( 1 -ethoxy- ethoxy )-4 -phenyl- 2- azetidinone (XXI) 3. Zn, CH3COOH. CH30H )(X1 +I 696 D Docetaxel 1. KoY'H, . THF CH, 0 I1 2. H3C-S-CI