tert-butyl hypobromite H3C,C-0-Br tert-butyl methoxy-3-phenyl- propane UI... sodium hyposulfite Ziprasidone hydrochloride u... tin1l chloride S-4-4-hydrozinobenzy1- 2-oxozolidinon
Trang 1Zipeprol Z 2201
Zimeldine
2 134 379 (AB HBssle; appl 12.4.1972; S-prior 28.4.1971)
alternative syntheses:
BE 835 802 (Astra; appl 21.1 1.1975; S-prior 21.1 1.1974)
SU 650 501 (Pharmastra; appl 21.5.1976)
Formulation(s): 100 mg, 200 mg (as dihydrochloride)
Trade Name(s):
D: Normud (Astra); wfm GB: Zelmid (Astra); wfm
Use: antitussive RN: 34758-83-3 MF: CZ3H3,N,O3 MW: 384.52 EINECS: 252-191-7
CN: 4-(2-methoxy-2-phenylethyl)-a-(methoxyphenylmethyl)-1-piperazineethanol
dihydrochloride
RN: 34758-84-4 MF: C2,H3,NzO3 2HCl MW: 457.44 EINECS: 252-192-2
LD,,: 44.3 mglkg (M, i.v.); 300 mglkg (M, p.0.);
32.7 mglkg (R, i.v.); 435 mglkg (R, p.0.);
228 mglkg (dog, p.0.)
tert-butyl hypobromite
(H3C),C-0-Br
tert-butyl
methoxy-3-phenyl- propane (UI)
Trang 22202 Z Ziprasidone hydrochloride
Rejerence(s):
US 3 7 18 650 (Mauvernay; 27.2.1973; F-prior 2.3.1970)
DE 2 109 366 (CERM; appl 30.9.1971; prior 27.2.1971)
Formulation(s): drg 75 mg; syrup 0.5 % (as dihydrochloride)
Trade Name(s):
F: Respilhe (Winthrop; 1973) I: Zitoxil (Italfarmaco; 1979)
Ziprasidone hydrochloride
(CP-88059-1)
Use: antipsychotic, dopamine D2- antagonist, 5-HT2-antagonist
RN: 138982-67-9 MF: C21H2,ClN40S HCl H 2 0 MW: 467.42
CN: ~-[2-[4-(l,2-Benzisothiazol-3-yl)-l-piperazinyl]ethyl]-6-chloro-l,3-dihydro-2H-indol-2-one
hydrochloride hydrate
base
RN: 146939-27-7 MF: CzIH2,ClN4OS MW: 412.95
hydrochloride
RN: 122883-93-6 MF: C,IH21ClN40S~ HCl MW: 449.41
mesyIate
RN: 18.5021-64-1 MF: C21H21ClN40S CH403S MW: 509.05
chloroocetyl chloride
0
H,c,;~,cH, '
H CF,COOH
c I , u triethylsilane,
trifluoroacetic
(2-chloroethy1)- oxindole (n)
Trang 3Ziprasidone hydrochloride Z 2203
I-(1,2-benziso-
thiazol-3-yl)-
piperozine (111)
1 POCI,
(\NH
2 ~ ~ 3
2 piperazine
2.5-dichloro-
taluene
Ziprasidone hydrochloride
I
H3c-C~CH, H3C-N,
CH, CH3
THF
,
tert-butoxybis-
rnethone
Xo2 H3C CH3COOH PN CI CH,COOH C I / ' V ~ '
IV + Ill - S,N, N , -+ V
borohydride
1 3 N HCI
2 SOCI2, C Y O H
3 No2Sp04, THF H 2 0
VI - 3 sodium hyposulfite
Ziprasidone hydrochloride
u
Trang 42204 Zolimidine
Reference(s):
a Howard, H.R et al.: J Labelled Compd Radiopharm (JLCRD4), 1994, 51
US 5 206 366 (Pfizer; 27.4.1993; USA-prior 26.8.1992)
EP 281 309 (Pfizer; appl 24.2.1988; WO-prior 2.3.1987)
b Urban, F.J et al: Synth Commun (SYNCAV) 26 (a), 1629-1638 (1996)
IJS 5 359 068 (Pfizer; 25.10.1994; USA-prior 28.6.1993)
monohydrate:
EP 586 191 (Pfizer; appl 25.8.1993; USA-prior 1.9.1992)
mesylate dihydrate salts:
WO 9 742 191 (Pfizer; appl 10.4.1997; USA-prior 7.5.1996)
cyclodextrin inclusion complexes:
EP 81 1 386 (Pfizer; appl 24.4.1997; USA-prior 7.5.1996)
Formulation(s): cps 20 mg, 40 mg, 60 mg, 80 mg
Trade Name(s):
USA: Zeldox (Pfizer)
Use: ulcer therapeutic RN: 1222-57-7 MF: C,4H,2N202S MW: 272.33 EINECS: 214-947-4
LD,,,: >4 glkg (M, p.0.);
3710 mglkg (R, p.0.)
CN: 2-[4-(methylsulfonyl)phenyl]imidazo[1,2-a]pyridine
I Zolirnidine
Refererzce(s):
GB 991 589 (Lab Bioterapico Milanese Selvi; valid from 23.7.1963; I-prior 30.4.1963)
Almirante, L et al.: J Med Chem (JMCMAR) 8, 305 (1965)
Formula~ion(s): cps 200 mg
Trade Narne(s):
1: Solimidin (Selvi); wfm USA: Mutil (Lakeside); wfm
Zolmitriptan
(31 1C90; BW-311C90)
ATC: N02CC03 Use: antimigraine agent, 5-HT,D-agonist RN: 139264-17-8 MF: C,,H2,N302 MW: 287.36
CN: (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone
monohydrochloride
RN: 139264-19-0 MF: C,6H2,N302 HCl MW: 323.82
racemic monohydrochloride
RN: 139346-15-9 MF: C,,H2,N302~ HCl MW: 323.82
Trang 5Zolmitriptan Z 2205
synthesis of intermediote 111:
1 S0CI2 CH,OH
HOOC
2 sodium borohydride
4-nitro-L-phenyl-
olonine (I)
1 KOH or NoOH
2 H2, Pd-C
3 NaN02 HCI
0 4 SnCI2 0 H
n + CI ,,l 0 /CCI3 - 2 hydrogen pollodium
3 sodium nitrite di~hosgene 4 tin(1l) chloride (S)-4-(4-hydrozinobenzy1)-
2-oxozolidinone hydrochloride (Ill)
or:
1 KOH or NoOH
2 H2 Pd-C
3 NoNO,, HCI
4 SnClp
2 hydrogen pollod~um
3 sodium nitrite phosgene
4 tin(l1) chloride
synthesis of intermediote V:
1 H20, KOH 0
2 Hz, Pd-C
2 hydrogen
pallodium benzyl
isocyanote
1 NoN02 HCI 0
2 SnCI, H
N 1 sodium nitrite ,
2 tin@) chloride '
(5)-5-(4-hydrozinobenzy1)-
2.4-imidozolidinedione hydrochloride (V)
butonol diethyl
ocetal (VI)
I
Trang 62206 Z Zolmitriptan
1 C2H50H, H20, A
2 H2C=0 H20 CH30H
3 NoCNBH3
4 FH3
111 +
2 formaldehyde
3 sodium cyonoborohydride 4-chlorabutanol 4 dimethylomine (WI)
diethyl ocetal (VII)
3-cyonoproponol
diethyl ocetal
1 PPE, CHC13, A
2 Hz Pd-C C2H50H VIIl
D
1 polyphosphote ester
2 hydrogen, pollodium, ethanol
1 C2H50H H20 A
2 Bo(OH), H20
v + V I - 2 borium hydroxide
HOOC
N-CH3 H3C
3-[3-(2-dimethylominoethyl)- 1H-indol-5-yl]-L-alanine (X)
2 sodium barahydride
3 diethyl carbonate, potassium
carbonote
alternative synthesis of X:
1 C2H50H H20 A
2 HzC=O H20 CH,OH
3 NoCNBH3
4 VIII
5 BO(OH)~, H20
v + vn b x
3 sodium cyonoborohydride
5 borium hydroxide
Reference(s):
WO 9 1 18 897 (The Wellcome Foundation; appl 12.12.1991; GB-prior 7.6.1990, 1.2.1991) Glenn, R.C et al.: J Med Chem (JMCMAR) 38,3566 (1995)
Trang 7Zolpidem Z 2207
synthesis of 4-dimethylaminobutanal diethyl acetal:
Desaty, K.: Croat Chem Acta (CCACAA) 36, 103, 107 (1964)
Somin, I.N et al.: J Org Chem (JOCEAH) 1,201 1 (1965)
Bhattacharyya, S.: Tetrahedron Lett (TELEAY) 35 (IS), 2401 (1994)
Harries et al.: Justus Liebigs Ann Chem (JLACBF) 410,65 (1915)
synthesis of 4-chlorobutanal diethyl acetal:
Loftfield: J Am Chem Soc (JACSAT) 73, 1365 (1951)
Anet et a].: Aust J Sci Res Ser A (AJSRA2) 3, 336 (1950)
Winterfeld et al.: Arch Pharm Ber Dtsch Pharm Ges (APBDAJ) 293, 325 (1960)
Tamelen, Van et al.: Bioorg Chem (BOCMBM) 5,283 (1976)
Formulation(s): f c tabl 2.5 mg; tabl 2.5 mg
Trade Narne(s):
D: Asco Top (Zeneca) GB: Zomig (Zeneca)
Zolpidem
(SL-80-0750-23N)
ATC: N05CF02 Use: hypnotic with affinity to benzodiazepine receptor RN: 82626-48-0 MF: C,9H21N,0 MW: 307.40
CN: N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide
tartrate (2:l)
RN: 99294-93-6 MF: C,,H2,N30 1/2C4H60, MW: 764.88
LD,,: 695 mg/kg (M, p.0.);
2700 m g k g (R, p.0.)
tartrate (1:l)
RN: 103188-50-7 MF: C,,H2,N,0 C4H,06 MW: 457.48
2-amino-5- bromomethyl 2-(4-methylpheny1)-6-
rnethylpyridine 4-methylphenyl methylimidozo[l -2-01-
ketone pyridine (I)
1 CH31
" 3 C
2 NoCN
r H3C
1 methyl iodide NC'
2 sodium cyonide
1 HCI, CH3COOH
2 P0Cl3
3 n
111 -b
2 phosphoryl
chloride
Trang 82208 Z Zomepirac
2.2-dimethoxy-
N.N-dimethyl-
ocetomide
Reference(s):
a EP 50 563 (Synthelabo; appl 15.10.1981; F-prior 22.10.1980)
DE 3 163 524 (Synthelabo; appl 15.10.198 1; F-prior 22.10.1980)
b EP 251 859 (Synthelabo; appl 17.6.1987; F-prior 27.6.1986)
2,2-dimethoxy-N,N-dimethylacetamide:
US 3 361 757 (Du Pont; 15.1 1.1965)
Formulation(s): f c tabl 10 mg; tabl 5 mg, 10 mg (as tartrate)
Trade Name(s):
D: Bikalm (Byk Gulden) Stilnox (SynthClabo; 1988) Stilnox (Synthelabo; 1990) Stilnox (Synthelabo) GB: Stilnoct (Lorex) J: Myslee (Fujisawa) F: Ivadal (Cipharm) I: Niotal (Synthelabo) USA: Ambien (Searle)
Use: analgesic, anti-inflammatory RN: 33369-31-2 MF: C,,H,,C1NO3 MW: 291.73 EINECS: 251-474-2
CN: 5-(4-chlorobenzoyl)- 1,4-dimethyl-1 H-pyrrole-Zacetic acid
sodium salt dihydrate
RN: 64092-49-5 MF: C,,H,,ClNNaO, 2H20 MW: 349.75
pyrrole-2-ocetote (I)
4-chlorobenzoyl
chloride
Trang 9Zonisamide Z 2209
11
quinoline copper chrornite ' I 0 0 m4
Zomepirac
Reference(s):
DE 2 102 746 (McNeil; appl 21.1.197 1 ; USA-prior 26.1.1970)
US 3 952 012 (McNeil; 20.4.1976; prior 16.2.1973, 26.1.1970, 1.7.1968, 26.7.1967)
Carson, J.R.; Wong, S.: J Med Chem (JMCMAR) 16, 172 (1973)
alternative syntheses:
BE 762 060 (McNeil; appl 26.1.1971; USA-prior 26.1.1970)
DOS 2 339 140 (McNeil; appl 2.8.1973; USA-piior 3.8.1972)
US 3 865 840 (McNeil; 11.2.1975; prior 16.2.1973, 26.7.1967, 1.7.1968, 26.1.1970)
Formulation(s): tabl 100 mg (as sodium salt dihydrate)
Trade Name(s):
D: Zornax (Cilag); wfm F: Zomax (Cilag); wfm USA: Zomax (McNeil); wfm
RN: 68291-97-4 MF: CuH,N203S MW: 212.23
LD,: 699 rnglkg (M, i.p.); 816 mglkg (M, i.v.); 1829 mglkg (M, p.0.); 1009 mglkg (M, s.c.);
733 rnglkg (R, i.p.); 672 mglkg (R, i.v.); 1992 mglkg (R, p.0.); 925 mglkg (R, s.c.);
1 glkg (dog, p.0.)
CN: 1,2-benzisoxazole-3-methanesulfonamide
monosodium salt
RN: 68291-98-5 MF: CuH,N2Na0,S MW: 234.21
1 P0Cl3
"
- -No
"Br sulfite ->-u II
1,2-benzisoxozole (I) isoxazole-3-methane-
sulfonote
Reference(s):
DE 2 825 410 (Dainippon; appl 9.6.1978)
US 4 172 896 (Dainippon; 30.10.1979; appl 5.6.1978)
Uno, H et al.: J Med Chem (JMCMAR) 22, 180 (1979)
Trang 102210 Z Zopiclone
synthesis of3-bromomethyl-1,2-benzisoxazole:
Uno, H et a].: Chem Pharm Bull (CPBTAL) 24,632 (1976)
Giannella, M et al.: Chim Ther (CHTPBA) 7, 127 (1972)
oral formulation:
JP 63 150 220 (Dainippon; appl 15.12.1986)
alternative synthesis:
Mohareb, R.M et a].: Z Naturforsch., B: Chem Sci (ZNBSEN) 45, 1067 (1990)
Formulation(s): powder 200 mglg; tabl 100 mg
Trade Narne(s):
J: Excegran (Dainippon;
1990)
Zopiclone
(RP-27267)
ATC: NOSBX; NOSCFO1 Use: anxiolytic, hypnotic RN: 43200-80-2 MF: C,,H,,CIN601 MW: 388.82 EINECS: 256-138-9
LD5,,: 580 mglkg (M, i.p.); 321 mg/kg (M, i.v.); 2174 mglkg (M, p.0.);
280 mglkg (R, i.v.); 827 mglkg (R, p.0.);
400 mglkg (dog, i.v.); 2500 mglkg (dog, p.0.)
CN: 4-methyl-1 -piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-py~olo[3,4- blpyrazin-5-yl ester
pyrozine-2,3- 2-amino-5- 3-(5-chloropyrtd-2-yl- 6-(5-chloropyrld-2-yI)-
d~corboxylic chloropyr~d~ne corbarnoyl)pyrilz~ne-2- 5,7-dioxo-6,7-dihydro-
4->1 - 1 -chlorocorbonyl-4-
methylpiperazine
0
Zopiclone
Referencefs):
DOS 2 300 491 (RhBne-Poulenc; appl 5.1.1973; F-prior 7.1.1972,9.9.1972)
US 3 862 149 (RhBne-Poulenc; 21.1.1975; F-prior 7.1.1972,9.9.1972)
Formulation(s): f c tabl 7.5 mg
Trade Name(s):
D: Ximovan (RhBne-Poulenc GB: Zimovane (RhBne-Poulenc J: Amoban (RhBne-Poulenc-
F: Imovane (Specia Groupe I: Imovane (RhBne-Poulenc
RhBne-Poulenc Rorer) Rorer; 1989)