HCL fluorobenzene 3-chloro-4-nitro- 3-chloro-4-nitro- benzoyl chloride 4'-fluorobenrophenone Refererlces: DOS 2 029 637 Janssen; appl.. 100 mg Flubendazole Trade Names: D: Flubenol
Trang 1Fluazacort F 87 1
1 HBr, AcOH
2 BrZ CHCI,
:: :' Br2, diomne
e NYCHz 3 DMF LiBr Li2c03
b
H
O H
(3~.5a.5'p)-2l-acetoxy-3-
hydroxy-2'-methyl-5H-
pregn-9(11)-eno[l7,16-dl-
oxozol-20-one (N)
(5'8)-21 -ocetoxy-2'-methyl-
S'H-pregna-1.4,9(11)-trieno[l7,16-dl-
oxazole-$20-diane (VI)
1 H3C-CO-NU-Br, HCIO,
2 NoOH
3 H2FZ THF
1 N-bromoacetarnide
Fluazocort
L
1 Ac,O, pyridine I KOH
2 I, N C X C ~ ~ N , ~
H3C N H CN
3 H~C-COOH ! N ( c ~ H ~ ) ~
2 rnesyl chlorrde 2 iodine, ozoisobutyronitrile
3 triethylommon~um acetate
(5a,5'@)-3@,1 Ig-dihydroxy-
2'-methyl-SH-pregnano-
[17,16-d]oxozol-20-one
(cf Deflozacort)
0
1 H3C.!-+Br , HCIO,
1 Cr03 2 NoOH
2 Br2 3 HF
3 LizC03 4 Ac20 pyridine
N - VI -,
1 N-brornoocetamide
Reference(s):
a DOS 1 618 613 (Lepetit; appl 7.1.1967; GB-prior 11.1.1966, 11.7.1966,29.9.1966)
US 3 461 119 (Lepetit; 12.8.1969; appl 1967; GB-prior 1.1 1.1966)
Trang 2872 F Flubendazole
sytlthesis of starting compound:
DE 1 568 971 (Gruppo Lepetit; appl 23.12.1966; GB-prior 11.1 l966, 11.7.1966,29.9.1966)
US 3 624 077 (Gruppo Lepetit; 30.1 1.1971; GB-prior 11.1.1966)
Nathansohn, G et al.: J Med Chem (JMCMAR) 10,799 (1967)
Nathansohn, G et al.: Gazz Chim Ital (GCITA9) 95, 1338 (1965)
review:
Nathanson, G et al.: Steroids (STEDAM) 13,365 (1969)
alternative synthesis of VI:
DOS 1 568 071 (Lepetit; appl 23.12.1966; GB-prior 11.1.1966, 11.7.1966,29.9.1966) DOS 1 568 972 (Lepetit; appl 23.12.1966; GB-prior 11.1.1966, 1 1.7.1966, 29.9.1966)
b Nathansohn, G et al.: J Med Chem (JMCMAR) 10,799 (1967)
Nathansohn, G et al.: Steroids (STEDAM) 13, 383 (1969)
Formulatior2(s): cream 0.025 %
Trade Name(s):
I : Azacortid crema (Lepetit)
Use: anthelmintic
RN: 31430-15-6 MF: C,,H,,FN,O, MW: 3 13.29 EINECS: 250-624-4
LD,,,: ~ 2 5 6 0 mg/kg (M, p.0.);
2560 mgkg (R, p.0.)
CN: [5-(4-fluorobenzoy1)-IH-benzimidazol-2-yl]cbamic acid methyl ester
1 NH3, CH30H,
sulfolone.125 O C
2 HZ Pd-C HCL
fluorobenzene 3-chloro-4-nitro- 3-chloro-4-nitro-
benzoyl chloride 4'-fluorobenrophenone
Refererlce(s):
DOS 2 029 637 (Janssen; appl 16.6.1970; USA-prior 20.6.1969)
US 3 657 267 (Janssen; 18.4.1972; appl 20.6.1969)
Raymaekers, A.H.M et al.: Arzneim.-Forsch (ARZNAD) 28,586 (1978)
3,4-diomino-4'- S-methyl- methyl
Formulation(s): susp 100 mglml; tabl 100 mg
Flubendazole
Trade Name(s):
D: Flubenol (Janssen); wfm F: Fluvermal (Janssen-Cilag)
lluorobenzophenone (1) isothioureo chloroformate
Trang 3P"
Fluclorolone acetonide F 873
Fluclorolone acetonide
(Flucloronide)
ATC: H02AB Use: topical glucocorticoid
RN: 3693-39-8 MF: C2,H,yC12FOs MW: 487.40 EINECS: 223-010-9
CN: (6a,l 1 P,16a)-9,l I-dichloro-6-fluoro-2l-hydroxy-16,17-[(I-methylethylidene)bis(oxy)]pregna- 1 ,4-diene- 3,20-dione
d
HJC-SOzCI pyridine DMF
21-0-acetyl-6.-fluoro-
16a-hydmxyhydrocortisone
ocetonide
1 CIZ CHCI3
3 KOH
b
1 chlorine
2, selenium dioxide
3 potassium hydroxide
( Fluclarolone occtonide I
Reference(s):
US 3 201 391 (Syntex; 17.8.1965; MEX-prior 18.2.1959, 20.10.1959)
starting material:
Mills, J.S et al.: J Am Chem Soc (JACSAT) 81, 1264 (1959)
Formulation(s): cream 0.025 %, 0.25 %
Trade Name(s):
F: Topilar (Syntex-Daltan); GB: Topilar (Syntex); wfm
wfm
Flucloxacillin
(J3oxacillin)
ATC: JOlCA 1Jse: antibiotic
RN: 5250-39-5 MF: CIyH,,C1FN3OSS MW: 453.88 EINECS: 226-051-0
CN: [2S-(2a,5a,6~)]-6-[[[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]carbonyl]amin]-3,3-dimethyl- 7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid
monosodium salt
RN: 1847-24-1 MF: C,,H16ClFN3NaOSS MW: 475.86 EINECS: 217-428-0
LD,,: 1360 mglkg (M, i.v.); 7600 mgkg (M, p.0.);
680 mglkg (R, i.v.); 1 1 glkg (R, p.0.);
670 mg/kg (dog, i.v.); >10 glkg (dog, p.0.)
Trang 48 7 4 F Fluconazole
2-chloro-6-fluoro-
benzaldehyde
CH, CH3
methyl
ocetoacetate
GB 987 299 (Beecharn; appl 17.10.1962; addition to GB 905 778 from 14.3.1961)
US 3 239 507 (Beecham: 8.3.1966; GB-prior 17.10.1962)
(11) 6-aminopenicillanic
For~nulation(s): cps 272 mg, 544 mg; vial 272 mg, 544 mg, 1088 mg, 2176 mg (as sodium salt hydrate)
Flucloxacillin
Trade Narne(s):
D: Flanomox (Wolfo-comb GB: Floxapen (SmithKline I: Infectrin (Pierrel)-comb Fluxapril (Leder1e)-comb Beecham) with ampicillin Staphylex (SmithKline Magnapen (SmithKline J: Culpen (Fujisawa) Beecham) Beecham)-comb Floxapen (Beecham)
Stafoxil (Yamanouchi)
acid
Fluconazole
(UK-49858)
ATC: J02ACOI; J02AX Use: antifungal (treatment of vaginal, oropharyngeal and atrophic oral candidiasis)
RN: 86386-73-4 MF: C,,H,,F,N,O MW: 306.28
LD,,,: >200 mg/kg (M, i.v.); 1408 mglkg (M, p.o.1;
>200 mg/kg (R, i.v.); 1271 mg/kg (R, p.0.);
>I00 mglkg (dog, i.v.); >300 mglkg (dog, p.0.)
CN: a-(2,4-difluoropheny l)-a-(IN-1,2,4-triazol-l-ylmethyl)-1H-1,2,4-triazole- 1-ethanol
Trang 5Fluconazole F 875
butyllithium
C I ~ C I
0
,
1 -3-dichloro- ocetone
1 H-1.2.4-
triozole (111)
F
Fluconazole
1,3-difluoro- 2.4-difluoro- 1 -3-dichloro-2-(2,4-difluoro-
benzene (I) phenyllithium phenyl)-2-proponol (11)
chloroacetyl a-chloro-2.4-difluoro- a-(1 H-l,2.4-triozol-1 -yl)-
chloride acetophenone 2,4-difluc~oacetophenone (N)
trirnethylsulfoxonium 1 -[2-(2.4-difluorophenyl)-
iodide 2,3-epoxypropyll- 1 H-
1.2.4-triozole
Reference(s):
GB 2 099 818 (Pfizer; appl 22.4.1982; prior 6.6.1981,4.3.1982)
EP 96 569 (Pfizer; appl: 6.6.1983; GB-prior 9.6.1982, 30.7.1982)
tablet formulation:
EP 178 682 (Schering Corp.; appl 23.4.1986; USA-prior 19.10.1984)
alternative synthesis:
ES 549 684 (Lazlo Int.; appl 6.12.1985)
ES 5 490 202 (Inke S A.; appl 19.1 1.1985)
US 5 710 280 (Dev Center Biotech Taiwan; 20.1.1998; appl 9.7.1996)
WO 9 703 971 (Apotex; appl 17.7.1996; NZ-prior 17.7.1995)
Formulation(s): cps 50 mg, 100 mg, 150 mg, 200 mg; susp 50 mg/5 ml; syrup 50 mgIl0ml; tabl 50 mg,
100 mg, 150 mg, 200 mg; vial 100 mg, 200 mg, 400 mg
Trade Name(s):
D: Diflucan (Pfizer) I: Biozolene (Bioindustria; Elazor (Sigma-Tau)
F: Triflucan (Pfizer; 1989) 1989) J: Diflucan (Pfizer Taito) GB: Diflucan (Pfizer; 1988) Diflucan (Roerig) USA: Diflucan (Pfizer; 1990)
Trang 6876 F Flucytosine
Use: fungicide
RN: 2022-85-7 MF: C4H4FN30 MW: 129.09 EINECS: 217-968-7
LD,,: 500 mg/kg (M, i.v.); > I 5 g/kg (M, p.0.);
>600 mgkg (R, i.v.); > I 5 g/kg (R, p.0.)
CN: 4-amino-5-fluoropyrimidin-2(IH)-one
H
POCIJ dimethylaniline
0 CI
2.4-dichloro- 5-fluoro- pyrimidine
5-fluoro-2- 4-chloro-5-fluoro-
methylthiourocii 2-methylthio-
(cf fiuorouracil pyrimidine
synthesis)
4-omino-2- chloro-5-fluoro- pyrimidine
a Duschinsky, R et al.: J Am Chem Soc (JACSAT) 79,4559 (1957)
Undheim, K.; Gacek, M.: Acta Chem Scand (ACHSE7) 23, (I), 294 (1969)
US 3 040 026 (Roche; 19.6.1962; appl 3.6.1959)
US 3 185 690 (Roche; 25.5.1965; prior 3.6.1959, 14.9.1961)
b US 2 945 038 (Roche; 12.7.1960; prior 26.9.1956)
US 2 802 005 (Roche; 6.8.1957; prior 26.9.1956)
medical use:
US 3 368 938 (Roche; 13.2.1968; prior 2.3.1962)
Formulation(s): cps 250 mg, 500 mg; tabl 500 mg; vial 2.5 g1250 rnl
Trade Name(s):
D: Ancotil Roche (ICN) GB: Alcobon (Roche); wfm J: Ancotil (Roche)
F: Ancotil (Roche) I: Ancotil (Roche) USA: Ancobon (Roche)
Fludarabine phosphate
(2-fluoro-ara-AMP)
ATC: LOlBB05 Use: antineoplastic, antimetabolite, treatment of chronic lymphocytic leucemia
RN: 75607-67-9 MF: C,,H,,FN,O,P MW: 365.21
LD,,,: 375 mglkg (M, i.p.); 1236 mgkg (M, i.v.)
CN: 2-fluoro-9-(5-O-phosphono-~-~-arabinofuranosyl)-9H-purin-6-amine
fludarabine
RN: 21679-14-1 MF: C,,H,,FNSO4 MW: 285.24 EINECS: 244-525-5
Trang 7Fludarabine phosphate F 877
k
H2N N
2,4,5,6-tetroornino- forrnornide 2-omino-
pyrimidine
orobinofuronose
adenine (I)
1 NoOCH,, CH,OH 1 BCI* CH,CI,
If Z
2 tetrofluaroboric acid 1 boron trichloride
sodium nitrite 2 phosphorus oxychloride,
triethyl phosphate
9-(2,3,5-tri-0-benzyl- Fludorobine 8-D-orobinofuronosyl)- phosphate 2-fluoroodenine
Reference(s):
US4 357 324 (Department of Health of USA; 2.1 1.1982; appl 24.2.1981)
synthesis of 9-P-D-arabinofuranosyl-2-fluoroadenine:
US 4 210 745 (Department of Health of USA; 1.7.1980; appl 20.1 1.1978; prior 10.3.1978,4.1 l978)
Montgomery, J.A et al.: J Heterocycl Chem (JHTCAD) 16, 157 (1979)
Montgomery, J.A.; Hewson, K.: J Med Chem (JMCMAR) 12,498 (1961)
synthesis of Zaminoadenine:
Robins, R.K et al.: J Am Chem Soc (JACSAT) 75,263 (1953)
Formulation(s): vial (lyo.) 5 mg, 50 mg
Trade Name(s):
D: Fludara (rneda; Schering) 'GR: Fludara (Schering)
F: Fludara (Schering) USA: Fludara (Berlex; 1991)
Trang 8878 F Fludrocortisone
S03CA05 Use: glucocorticoid
IRN: 127-31-1 MF: C2,H2,FOs MW: 380.46 EINECS: 204-833-2
LD,,: 170 mglkg (M, i.p.)
CN: (1 1 P)-9-fluoro-ll,l7.21-trihydroxypregn-4-ene-3,20-dione
acetate
RN: 514-36-3 MF: C,,H,,FO, MW: 422.49 EINECS: 208-180-4
LD,,: >I glkg (R, p.0.)
3 s r
' H $ N'
1 N-bromo- ocetamide
/ hydrocortisone 21-ocetote
H2F2
& I C H 3 onhydrous ;130, b or HCIJ/THFc or C H C I ~ / H ~ O / H C I O ~ ~ + I1
me^ H
21-ocetoxy-3.20-dioxo-98.118-
epoxy-17-hydroxy-4-pregnene ( I )
( fludrocortisone ocetote (11) Fludrocortisone
Refennce(s):
a Fried, J.; Sabo, E.F.: J Am Chem Soc (JACSAT) 76, 1455 (1954)
b GB 792 224 ( O h Mathieson; appl 1954; USA-prior 1954)
c DE 1 035 133 (Merck & Co.; appl 1956; USA-prior 1955)
Hirschmann, R.F et al.: J Am Chem Soc (JACSAT) 78,4956 (1956)
d US 2 894 007 (Merck & Co.; 7.7.1959)
e DE 1 028 572 (Schering AG; appl 2 1.1.1 957)
synthesis of hydrocortisone acetate:
Fried, J.; Sabo, E.F.: J Am Chem Soc (JACSAT) 75,2273 (1953)
US 2 771 475 (Upjohn; 1956, appl 1953)
GB 792 224 (Olin Mathieson; appl 1954; USA-prior 1954)
alternative syntheses:
US 2 771 475 (Upjohn; 1956; appl 1953)
US 2 799 688 (Upjohn; 1957; appl 1954)
US 2 852 51 1 (Olin Mathieson; 1958; prior 1953)
US 4 041 055 (Upjohn; 9.8.1977; appl 17.1 1 l975)
Trang 9Fludroxycortide F 879
Formulation(s): ear drops 8 mgI8 ml in comb with polymyxin B; ointment 0.001 %; tabl 0.1 mg (as acetate)
Trade Name(s):
D: Astonin H (Merck) F: Panotile (Zambon)-comb USA: Florinef (Apothecon) Fludrocortison (Bristol- GB: Florinef (Bristol-Myers
Myers Squibb) Squibb; as acetate)
Panotile (Zambon)-comb J: Florinef (Bristol Squibb)
Fludroxycortide
(Flurandrenolide)
ATC: D07AC07 Use: glucocorticoid, anti-inflammatory
RN: 1524-88-5 MF: C24H33FOh MW: 436.52 EINECS: 216-196-8
CN: (6a,11 ~,16a)-6-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione
21-acetoxy-16a.17-epoxy-
3P-hydroxy-20-0x0-5-pregnene
(from pregnenolone)
0 , CH2C12, - 80 "C b &FH3
hydrogen N-bromo-
fluoride ocetamide H ti
F
1 Cr03
2 HBr, CH3COOH
1 CH3COOK CH3COOH
2 No2C05 CH30H
I , 11
1 , chromium(VI) oxide
2 acetic anhydride
microbiological hydroxylation
[Arthrobotrys s u p e r b 0 vor oligospora (ATCC 11572)]
or [Cunninghamello blakesleeana (ATCC 8688b)I
0 z
o=tcH3
CH3
ocetone
HCIO,
Trang 10880 F Flufenamic acid
Reference(s):
a US 3 014 938 (Syntex; 26.12.1961; appl 23.8.1960; MEX-prior 7.9.1959)
US 3 119 749 (Syntex; 28.1.1964; appl 17.1 1.1961; MEX prior 7.6.1961)
US 3 124 571 (Syntex; 10.3.1964; MEX-prior 26.1.3960)
starting material:
Julian, P.L.: J Am Chem Soc (JACSAT) 72,5145 (1950)
US 2 678 932 (Sterling Drug; 1954; prior 1951)
b US 3 126 375 (Syntex; 24.3.1964; appl 11.6.1959; MEX-prior 13.6.1958)
DE 1 131 213 (Syntex; appl 6.6.1959; MEX-prior 13.6.1958)
alternative syntheses:
Mills, J.S et al.: J Am Chem Soc (JACSAT) 82, 3399 (1960); 81, 1264 (1959)
[JS 3 203 869 (Syntex; 31.8.1965; MEX-prior 11.10.1962)
Formulation(s): lotion 0.05 % (15 ml, 60 ml); tape 4pg/cm2
Trade Name(s):
D: Sermaka (Lilly) I: Drenison (Lilly); wfm J: Drenison Q (Lilly-
GB: Drenison (Lilly); wfm Drenison Neomicina Dainippon)
Haclan (Dista); wfm (Li1ly)-comb.; wfm USA: Cordran (Oclassen)
(Acide flufenamique) Use: anti-inflammatory, antirheumatic
RN: 530-78-9 MF: C14HloF1N02 MW: 281.23 EINECS: 208-494-1
LD,,: 158mg/kg(M,i.v.);490mglkg(M,p.o.):
98 m g k g (R, i.v.); 249 mglkg (R, p.0.)
CN: 2-[[3-(trifluoromethyl)phenylJamino]benzoic acid
aluminum salt
RN: 16449-54-0 MF: C4,H,AIF9N306 MW: 867.66 EINECS: 240-498-9
LD,,,: 1460 mglkg (M, p.0.);
550 mglkg (R, p.0.)
2-chloro- 3-trifluoro-
benzoic methylonilhe
ocid
COOH
Flufenornic ocid
I
Reference (s):
FR 1 341 M (Parke Davis; appl 1 1.8.1961)
Moffett, R.B.; Aspergen, B.D.: J Am Chem Soc (JACSAT) 82, 1605 (1960)
salts with amines:
DOS 2 758 787 (T Eckert; appl 29.12.1977)
Formulation(s): ointment 3 g/100 g (3 %); sol 25 mglg
Trade Name(s):
D: Algesalona (Sohay)-comb Rheuma Lindofluid Meralen (Merrell); wfm
Dignodolin (Sankyo) (Lindopharm) I: Mobilisin (Luitpold)-comb Mobilisin (Sankyo)-comb F: Arlef (Parke Davis); wfrn J: Achless (Tatsumi)
GB: Arlef (Parke Davis); wfm Arlef (Parke Davis-Sankyo)