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Friday 5 August 2016

MICONAZOLE NITRATE , Миконазол , ミコナゾール硝酸塩


Miconazole

            C18H14Cl4N2O                         416.13             [22916-47-8]

Miconazole Nitrate


            C18H14Cl4N2O.HNO3              479.14             [22832-87-7]


ミコナゾール硝酸塩 JP16
Miconazole Nitrate

C18H14Cl4N2O▪HNO3 : 479.14
[22832-87-7]
















click on above image for clear view










MORE GRAPHS


13C





1D 1H, n/a spectrum for Miconazole

2D [1H,1H]-TOCSY  BELOW

2D [1H,1H]-TOCSY, n/a spectrum for Miconazole

1D DEPT90

1D DEPT90, n/a spectrum for Miconazole

1D DEPT135

1D DEPT135, n/a spectrum for Miconazole


2D [1H,13C]-HSQC

2D [1H,13C]-HSQC, n/a spectrum for Miconazole



2D [1H,13C]-HMBC


2D [1H,13C]-HMBC, n/a spectrum for Miconazole

2D [1H,1H]-COSY

2D [1H,1H]-COSY, n/a spectrum for Miconazole

2D [1H,13C]-HMQC

2D [1H,13C]-HMQC, n/a spectrum for Miconazole
Miconazole is an imidazole antifungal agent, developed by Janssen Pharmaceutica, commonly applied topically to the skin or tomucous membranes to cure fungal infections. It works by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes. It can also be used against certain species of Leishmania protozoa which are a type of unicellular parasites that also contain ergosterol in their cell membranes. In addition to its antifungal and antiparasitic actions, it also has some antibacterialproperties. It is marketed in various formulations under various brand names.
Miconazole is also used in Ektachrome film developing in the final rinse of the Kodak E-6 process and similar Fuji CR-56 process, replacing formaldehydeFuji Hunt also includes miconazole as a final rinse additive in their formulation of the C-41RA rapid access color negative developing process.
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[1]







ALTERNATIVE ROUTES beginning with the racemic raw material will likely be more costly or more time-consuming to develop, Cox says. Crystallization might be tricky because the stereogenic center does not have a group that can readily undergo acid-base chemistry. Catalytic asymmetric chemistry will necessitate converting the raw material to an appropriate substrate and identifying effective, as well as usable, chemical catalysts or biocatalysts.
What happens to the unwanted enantiomer also depends on the economics. Reracemizing and feeding the racemate back into the process is ideal but not always practical. In the miconazole case, the raw material costs $32 per kg. It is unlikely that reracemizing would be less costly in this example, Cox explains.
People should not forget that the goal of chiral technologies--enantiopure product--also may be achieved with chemistry that already exists, notes David R. Dodds, founder of Dodds & Associates LLC, Manlius, N.Y., a consulting service for biotechnology and chemical companies. Process chemists seek the most robust, most productive, and least expensive synthetic route and aim to find it as fast as possible. Any reaction that can help reach this goal is useful. It is the overall process cost that will dictate which reactions will be used. And that cost covers not only reagents but also waste streams, utilities, equipment use, unit operations, and downstream requirements. Thus, it may be more commercially attractive to replace an elegant but expensive single reaction with several more mundane ones that have a lower total cost, he says. Such a situation is likely to arise when an asymmetric step requires an expensive chiral catalyst or chiral auxiliary.

Brief background information

SaltATCFormulaMMCAS
-A01AB09 
A07AC01 
D01AC02 
G01AF04 
J02AB01 
S02AA13
18 H 14 Cl 4 N 2 O416.14 g / mol22916-47-8
mononitrateA01AB09 
A07AC01 
D01AC02 
G01AF04 
J02AB01 
S02AA13
18 H 14 Cl 4 N 2 O ⋅ HNO 3479.15 g / mol22832-87-7

Using

  • antifungal agent for topical use
  • antimycotic agent

Classes substance

  • Imidazoles, 1- (hlorfenetil) imidazoles

synthesis Way

Synthesis of a)

trade names

A countryTradenameManufacturer
GermanyCastellaniHollborn
DaktarMcNeil
Derma-MikotralRosen Pharma
FungurHEXAL
Gyno-DaktarJanssen-Cilag, 1974
Gyno-MikotralRosen Pharma
Infektozoor MundgelInfectopharm
Mikobetabetapharm
MikotarDermapharm
MikodermEngelhard
MikotinArdeypharm
VobamikAlmirall Hermal
FranceDaktapinJanssen-Cilag
Gyno-DaktapinJanssen-Cilag
LoramikBioalliance
United KingdomGyno-DaktapinJanssen-Cilag
ItalyDaktapinJanssen-Cilag
MikonalEcobi
MikotefLPB
MidermMendelejeff
NizakolPS Pharma
PivanazoloMedestea
PrilaginSofar
JapanFloridMochida
USAFungoidPedinol
UkraineGІNEZOL 7Sagmel, Іnk., USA
MІKONAZOL-DarnitsaCJSC "Farmatsevtichna FIRMA" Darnitsa ", m. Kyiv, Ukraine
MІKOGELBAT "Kiїvmedpreparat", m. Kyiv, Ukraine
various generic drugs

Formulations

  • ampoule 200 mg / 20 ml;
  • cream 1%, 2 g / 100 g 20 mg / g;
  • losyon 1%;
  • ointment 1%;
  • 2% oral gel;
  • Powder 2 g / 100 g 20 mg / g (in the form mononitrate);
  • solution of 20 mg / ml;
  • 100 mg suppositories;
  • Tablets of 250 mg (free base form);
  • vaginal cream 20 mg / g;
  • bottles of 400 mg / 40 ml

references

  1. Synthesis of a)
    • DAS 1,940,388 (Janssen; appl 8.8.1969;. USA-prior 19.8.1968, 23.7.1969.).
    • US 3,717,655 (Janssen; 20.2.1973; appl 19.8.1968.).
    • US 3,839,574 (Janssen; 1.10.1974; prior 23.7.1969.).

Miconazole nitrate was prepared by Godefori et al [5­-7]. Imidazole 1 was coupled with brominated 2,4‑dichloroacetophenone 2 and the resulting ketonic product 3 was reduced with sodium borohydride to its corresponding alcohol 4. The latter compound 4 was then coupled with 2,4-dichlorotoluene by sodium borohydride in hexamethylphosphoramide (an aprotic solvent) which was then extracted with nitric acid to give miconazole nitrate.


2-     Miconazole was also prepared by Molina Caprile [8] as follows:

Phenyl methyl ketone 1 was brominated to give 1-phenyl-2-bromoethanone 2. Compound 2 was treated with methylsulfonic acid to yield the corresponding methylsulfonate 3. Etherification of 3 gave the a‑benzyloxy derivative 4 and compound 4 was then chlorinated to give the 2,4‑dichlorinated derivative in both aromatic ring systems 5. Compound 5 reacted with imidazole in dimethylformamide to give miconazole 6 [7] which is converted to miconazole nitrate.

3-     Ye et al reported that the reduction of 2,4-dichlorophenyl-2-chloroethanone 1 with potassium borohydride in dimethylformamide to give 90% a‑chloromethyl-2,4-dichlorobenzyl alcohol 2. Alkylation of imidazole with compound 2 in dimethyl­formamide in the presence of sodium hydroxide and triethylbenzyl ammonium chloride, gave 1-(2,4‑dichlorophenyl-2-imidazolyl)ethanol 3 and etherification of 3 with 2,4-dichlorobenzyl chloride under the same condition, 62% yield of miconazole [9].


4-     Liao and Li enantioselectively synthesized and studied the antifungal activity of optically active miconazole and econazole. The key step was the enantioselective reduction of 2‑chloro-1-(2,4-dichlorophenyl)ethanone catalyzed by chiral oxazaborolidine [10].

5-     Yanez et al reported the synthesiz of miconazole and analogs through a carbenoid intermediate. The process involves the intermolecular insertion of carbenoid species to imidazole from a‑diazoketones with copper acetylacetonate as the key reaction of the synthetic route [11].
5-11 as 1-7
1.             E.F. Godefori and J. Heeres, Ger. Pat. 1,940,388 (1970).
2.             E.F. Godefori and J. Heeres, U.S. Pat. 3,717,655 (1973).
3.             E.F. Godefori, J. Heeres, J. van Cutsem and P.A.J. Janssen, J. Med. Chem., 12, 784 (1969).
4.             F. Molina Caprile, Spanish Patent ES 510870 A1 (1983).
5.             B. Ye, K. Yu and Q. Huang, Zhongguo Yiyao Gongye Zazhi, 21, 56 (1990).
6.             Y.W. Liao and H.X. Li, Yaoxue Xuebao, 28, 22 (1993).
7.             E.C. Yanez, A.C. Sanchez, J.M.S. Becerra, J.M. Muchowski and C.R. Almanza, Revista de la Sociedad Quimica de Mexico, 48, 49 (2004).
Miconazole

Title: Miconazole
CAS Registry Number: 22916-47-8
CAS Name: 1-[2-(2,4-Dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole
Additional Names: 1-[2,4-dichloro-b-[(2,4-dichlorobenzyl)oxy]phenethyl]imidazole
Molecular Formula: C18H14Cl4N2O
Molecular Weight: 416.13
Percent Composition: C 51.95%, H 3.39%, Cl 34.08%, N 6.73%, O 3.84%
Literature References: Prepn: E. F. Godefroi et al., J. Med. Chem. 12, 784 (1969); E. F. Godefroi, J. Heeres, DE 1940388;eidem, US 3717655 (1970, 1973 to Janssen). Clinical evaluation: Brugmans et al., Arch. Dermatol. 102, 428 (1970); Godts et al.,Arzneim.-Forsch. 21, 256 (1971). Review: P. Janssen, W. Van Bever, in Pharmacological and Biochemical Properties of Drug Substances vol. 2, M. E. Goldberg, Ed. (Am. Pharm. Assoc., Washington, DC, 1979) pp 333-354; R. C. Heel et al., Drugs 19, 7-30 (1980).
Derivative Type: Nitrate
CAS Registry Number: 22832-87-7
Manufacturers' Codes: R-14889
Trademarks: Aflorix (Gramon); Albistat (Ortho); Andergin (ISOM); Brentan (Janssen); Conoderm (C-Vet); Conofite (Mallinckrodt); Daktar (Janssen); Daktarin (Janssen); Deralbine (Andromaco); Dermonistat (Ortho); Epi-Monistat (Cilag); Florid (Mochida); Fungiderm (Janssen); Fungisdin (Isdin); Gyno-Daktarin (Janssen); Gyno-Monistat (Cilag-Chemie); Micatin (J & J); Miconal Ecobi (Ecobi); Micotef (LPB); Monistat (Cilag-Chemie); Prilagin (Gambar); Vodol (Andromaco)
Molecular Formula: C18H14Cl4N2O.HNO3
Molecular Weight: 479.14
Percent Composition: C 45.12%, H 3.16%, Cl 29.60%, N 8.77%, O 13.36%
Properties: Crystals, mp 170.5° (Godefroi, Heeres, 1970); 184-185° (Godefroi).
Melting point: mp 170.5° (Godefroi, Heeres, 1970); 184-185° (Godefroi)
Derivative Type: (+)-Form nitrate
Properties: mp 135.3°. [a]D20 +59° (methanol).
Melting point: mp 135.3°
Optical Rotation: [a]D20 +59° (methanol)
Derivative Type: (-)-Form nitrate
Properties: mp 135°. [a]D20 -58° (methanol).
Melting point: mp 135°
Optical Rotation: [a]D20 -58° (methanol)
Therap-Cat: Antifungal (topical).
Therap-Cat-Vet: Antifungal (topical).
Keywords: Antifungal (Synthetic); Imidazoles.

References

  1. Jump up^ "WHO Model List of EssentialMedicines" (PDF)World Health Organization. October 2013. Retrieved 22 April 2014.
  2. Jump up^ British National Formulary '45' March 2003
  3. Jump up^ "Strange Beauty: Monistat Effectively Increases Hair Growth?". Black Girl With Long Hair. Retrieved 12 April 2012.
  4. Jump up^ Ju, Jiang; Tsuboi, Ryoji; Kojima, Yuko; Ogawa, Hideoki (2005). "Topical application of ketoconazole stimulates hair growth in C3H/HeN mice"Journal of dermatology32: 243–247.
  5. Jump up^ S., Venturoli; O. Marescalchi; F. M. Colombo; S. Macrelli; B. Ravaioli; A. Bagnoli; R. Paradisi; C. Flamigni (April 1999). "A Prospective Randomized Trial Comparing Low Dose Flutamide, Finasteride, Ketoconazole, and Cyproterone Acetate-Estrogen Regimens in the Treatment of Hirsutism"The Journal of Clinical Endocrinology and Metabolism84 (4): 1304–1310. doi:10.1210/jc.84.4.1304. Retrieved 12 April 2012.
  6. Jump up^ Duret C, Daujat-Chavanieu M, Pascussi JM, Pichard-Garcia L, Balaguer P, Fabre JM, Vilarem MJ, Maurel P, Gerbal-Chaloin S (2006). "Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor". Mol. Pharmacol70 (1): 329–39. doi:10.1124/mol.105.022046PMID 16608920.
  7. Jump up^ Najm, Fadi J.; Madhavan, Mayur; Zaremba, Anita; Shick, Elizabeth; Karl, Robert T.; Factor, Daniel C.; Miller, Tyler E.; Nevin, Zachary S.; Kantor, Christopher (2015-01-01)."Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo"Nature522 (7555). doi:10.1038/nature14335.
  8. Jump up^ United States Patent 5461068

External links

Medical

Photographic


Miconazole
Miconazole2DCSD.svg
Miconazole ball-and-stick.png
Systematic (IUPAC) name
(RS)-1-(2-(2,4-Dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl)-1H-imidazole
Clinical data
Trade namesDesenex, Monistat, Zeasorb-AF
AHFS/Drugs.comMonograph
MedlinePlusa601203
Pregnancy
category
  • AU: A
  • US: C (Risk not ruled out)
  • In Australia, it is category A when used topically. In the US, the pregnancy category is C for oral and topical treatment.
Routes of
administration
topicalvaginalsublabial,oral
Legal status
Legal status
  • AU: S2 (Pharmacy only)
  • UK: POM (Prescription only)
  • US: OTC
  • Schedule 2 in Australia for topical formulations, schedule 3 (Aus) for vaginal use and for oral candidiasis, otherwise schedule 4 in Australia
Pharmacokinetic data
Bioavailabilityn/a
Metabolismn/a
Biological half-lifen/a
Excretionn/a
Identifiers
CAS Number22916-47-8 Yes
ATC codeA01AB09 (WHO)A07AC01 (WHO)D01AC02 (WHO)G01AF04 (WHO)J02AB01 (WHO)S02AA13 (WHO)
PubChemCID 4189
IUPHAR/BPS2449
DrugBankDB01110 Yes
ChemSpider4044 Yes
UNII7NNO0D7S5M Yes
KEGGD00416 Yes
ChEBICHEBI:6923 Yes
ChEMBLCHEMBL91 Yes
Chemical data
FormulaC18H14Cl4N2O
Molar mass416.127 g/mol
ChiralityRacemic mixture



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