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

2D [1H,1H]-TOCSY  BELOW

1D DEPT90

1D DEPT135

2D [1H,13C]-HSQC

2D [1H,13C]-HMBC

2D [1H,1H]-COSY

2D [1H,13C]-HMQC

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 formaldehyde. Fuji 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

Salt	ATC	Formula	MM	CAS
-	A01AB09  A07AC01  D01AC02  G01AF04  J02AB01  S02AA13	C 18 H 14 Cl 4 N 2 O	416.14 g / mol	22916-47-8
mononitrate	A01AB09  A07AC01  D01AC02  G01AF04  J02AB01  S02AA13	C 18 H 14 Cl 4 N 2 O ⋅ HNO 3	479.15 g / mol	22832-87-7

Using

• antifungal agent for topical use
• antimycotic agent

Classes substance

• Imidazoles, 1- (hlorfenetil) imidazoles

synthesis Way

Synthesis of a)

trade names

A country	Tradename	Manufacturer
Germany	Castellani	Hollborn
	Daktar	McNeil
	Derma-Mikotral	Rosen Pharma
	Fungur	HEXAL
	Gyno-Daktar	Janssen-Cilag, 1974
	Gyno-Mikotral	Rosen Pharma
	Infektozoor Mundgel	Infectopharm
	Mikobeta	betapharm
	Mikotar	Dermapharm
	Mikoderm	Engelhard
	Mikotin	Ardeypharm
	Vobamik	Almirall Hermal
France	Daktapin	Janssen-Cilag
	Gyno-Daktapin	Janssen-Cilag
	Loramik	Bioalliance
United Kingdom	Gyno-Daktapin	Janssen-Cilag
Italy	Daktapin	Janssen-Cilag
	Mikonal	Ecobi
	Mikotef	LPB
	Miderm	Mendelejeff
	Nizakol	PS Pharma
	Pivanazolo	Medestea
	Prilagin	Sofar
Japan	Florid	Mochida
USA	Fungoid	Pedinol
Ukraine	GІNEZOL 7	Sagmel, Іnk., USA
	MІKONAZOL-Darnitsa	CJSC "Farmatsevtichna FIRMA" Darnitsa ", m. Kyiv, Ukraine
	MІKOGEL	BAT "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).

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 dermatology. 32: 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 Metabolism. 84 (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. Pharmacol. 70 (1): 329–39. doi:10.1124/mol.105.022046. PMID 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". Nature. 522 (7555). doi:10.1038/nature14335.
8. Jump up^ United States Patent 5461068

External links

Medical

• Micatin
• Miconazole (National Institutes of Health)
• United States Patent 5461068 Imidazole derivative tincture and method of manufacture

Photographic

• Kodak process E6 Ektachrome (color transparency) processing manual Z-119
• Kodak process E6 Q-LAB processing manual Z-6 (more details than processing manual Z119 above)

Miconazole

Systematic (IUPAC) name
(RS)-1-(2-(2,4-Dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl)-1H-imidazole
Clinical data
Trade names	Desenex, Monistat, Zeasorb-AF
AHFS/Drugs.com	Monograph
MedlinePlus	a601203
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	topical, vaginal, sublabial,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
Bioavailability	n/a
Metabolism	n/a
Biological half-life	n/a
Excretion	n/a
Identifiers
CAS Number	22916-47-8
ATC code	A01AB09 (WHO)A07AC01 (WHO)D01AC02 (WHO)G01AF04 (WHO)J02AB01 (WHO)S02AA13 (WHO)
PubChem	CID 4189
IUPHAR/BPS	2449
DrugBank	DB01110
ChemSpider	4044
UNII	7NNO0D7S5M
KEGG	D00416
ChEBI	CHEBI:6923
ChEMBL	CHEMBL91
Chemical data
Formula	C18H14Cl4N2O
Molar mass	416.127 g/mol
Chirality	Racemic mixture

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