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CONAZOLE SERIES 2/2

CONAZOLE

CONAZOLE SERIES



1 TERCONAZOLE
2 KETOKONAZOLE 2S 4R
3 ISAVUCONAZOLE
4 TIOCONAZOLE
5 FOSRAVUCONAZOLE
6 RAVUCONAZOLE
7 EFINACONAZOLE
8 ALBACONAZOLE
9 BUTOCONAZOLE

PART 1..........http://drugsynthesisint.blogspot.in/p/conazole.html


PART 2
10 VORICONAZOLE
11 POSACONAZOLE
12





PART 2





10
 VORICONAZOLE





ChemSpider 2D Image | Voriconazole | C16H14F3N5O.
 VORICONAZOLE
CAS 137234-62-9
 (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol

Chemical Names: Voriconazole; Vfend; 137234-62-9; UK-109496; Voriconazol; Voriconazolum 
CAS  137234-62-9
(aR,bS)-a-(2,4-Difluorophenyl)-5-fluoro-b-methyl-a-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimideethanol
 2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
Manufacturers' Codes: UK-109496
Trademarks: Vfend (Pfizer)
MF: C16H14F3N5O
MW: 349.31
Percent Composition: C 55.01%, H 4.04%, F 16.32%, N 20.05%, O 4.58%
Properties: mp 127°. [a]D25 -62° (c = 1 in methanol).
Melting point: mp 127°
Optical Rotation: [a]D25 -62° (c = 1 in methanol)
Therap-Cat: Antifungal (systemic)



 Voriconazole (vor-i-KON-a-zole, brand name Vfend, Pfizer) is a triazole antifungal medication that is generally used to treat serious, invasive fungal infections. These are generally seen in patients who are immunocompromised, and include invasive candidiasis, invasive aspergillosis, and certain emerging fungal infections
 
 


1H NMR......... http://file.selleckchem.com/downloads/nmr/S144202-Voriconazole-HNMR-Selleck.pdf
1H NMR DMSO-d6, peak at 3.3 is HOD


m.p=134
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 
9.04 (1H), 
8.84 (1H), 
8.23 (1H), 
7.61 (1H), 
7.28 (1H), 
7.17 (1H), 
6.91 (1H), 
5.97 (1H), 
4.80 (1H), 
4.34 (1H), 
3.93 (1H), 
1.1 (3H).............US8263769



13 C NMR
DMSO-d6



 1H NMR PREDICT


 





 13C NMR PREDICT




COSY PREDICT


HMBC PREDICT






HPLC


Voriconazole, (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol having the structure of formula (I), is an antifungal drug used for preventing or treating fungal infection, e.g., human local fungal infection caused by candida, trichophyton, microspourum or epidemophyton; mucosal infection, by candida albicans (e.g., thrush and candidiasis); and whole body fungal infection, by aspergilus.

Figure US08263769-20120911-C00001
Voriconazole has two asymetric carbon atoms, and therefore, 4 stereoisomers, enantiomers of two diastereomeric pairs are involved in the preparation thereof which is generally conducted by a) separating an enantiomeric pair having (2R,3S) and (2S,3R) configurations; and then b) separating the (2R,3S)-stereoisomer using an optically active acid (e.g., R-(−)-10-camphosulfonic acid). The structural specificity and instability under a basic condition make the stereoselective synthesis of voriconazole difficult.
To date, only two methods for preparing voriconazole have been reported. One is based on a coupling reaction using an organic lithium salt, and the other, on Reformatsky-type coupling reaction.
For example, Korean Patent No. 1993-0011039 and European Patent No. 0,440,372 disclose a method shown in Reaction Scheme A for preparing the desired enantiomeric pair by a) adding an organic lithium derivative of 4-chloro-6-ethyl-5-fluoropyrimidine to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone at −70° C.˜−50° C. to obtain an enantiomer mixture; and b) separating the desired enantiomer by chromatography.

Figure US08263769-20120911-C00002
However, this coupling reaction using a strong base such as LDA or NaHMDS produces (2R,3S)/(2S,3R) and (2R,3R)/(2S,3S) diastereomers in a mole ratio of 1.1:1 without stereoselectivity, and the desired (2R,3S)/(2S,3R)-enantiomeric pair is isolated in a yield of only 12˜25%. Further, the lithium salt used in the reaction is difficult to be applied to mass production because of the required anhydrous condition at −78° C.
PCT Publication No. WO 2006/065726 discloses a method shown in Reaction Scheme B for preparing the desired enantiomeric pair by repeating the procedure of Reaction Scheme A except for using a different solvent.

Figure US08263769-20120911-C00003
However, despite the merit of this reaction which allows the separation of the desired enantiomeric pair by crystallization, it is hampered by the same problems associated with Reaction Scheme A and the yield of the desired enantiomeric pair is only 26%.
In order to solve the problems, as shown in Reaction Scheme C, Korean Patent Publication No. 1999-0036174 and U.S. Pat. No. 6,586,594 B1 disclose a method for preparing voriconazole by conducting Reformatsky-type reaction to enhance the stereoselectivity and yield, and then reductively removing the chlorine substituent in the presence of a palladium catalyst.

Figure US08263769-20120911-C00004
In this reaction, the (2R,3S)/(2S,3R)- and (2R,3R)/(2S,3S)-enantiomeric pairs were formed in a mole ratio of 9:1, and the yield of the isolated voriconazole hydrochloride was as high as 65%. However, the pyrimidine derivative used as a starting material is difficult to remove when remains unreacted, which leads to the lowering of the product purity.
Further, the literature ([Organic Process Research & Development 2001, 5, 28-36], Pfizer Inc.) teaches that the chlorine substituent of the pyrimidine derivative adversely influences the coupling reaction pattern as shown in Reaction Scheme D and Table 1.

Figure US08263769-20120911-C00005

TABLE 1

Reformatsky-type reaction of compounds (VI, VII) and (IV)

Compound Compound Unreacted Debrominated Compound Compound
Pyrimidine (VIII) (%) (IX) (%) pyrimidine (%) pyrimidine (%) (X) (%) (XI) (%)

Compound 47.5 24.0 0.0 15 4.3 9.2
(VI)
Compound 5.3 4.6 8.5 28 0.0 51.6
(VII)

Example 1 of Korean Patent Publication No. 1999-0036174 (see Reaction Scheme C) shows that the (2R,3S)/(2S,3R)- and (2R,3R)/(2S,3S)-enantiomeric pairs were obtained in a mole ratio of 10:1, but the product mixture contained unreacted compound of formula (IV) (7%) and unknown byproduct suspected to be the compound of formula (XI) (14%). Thus, the procedure of Reaction Scheme C gives an impure product mixture, the isolation of the desired product by recrystallization giving only a yield of 40˜45%.

 MORE..................


In the synthesis of Voriconazole, it is thought that two important steps are step i) of preparing the pyrimidine derivative as an intermediate for use in the subsequent coupling reaction with high yield and high purity, and step ii) of increasing stereoselectivity in carrying out the coupling reaction between the pyrimidine derivative and the ketone derivative to obtain the resultant tertiary alcohol with high purity and high yield.
First, the pyrimidine derivative has been prepared as depicted in the following Reaction Scheme 1 under reflux without any solvent according to Korean Patent No. 1993-0011039 and EP 0440372. It is reported that the yield of pyrimidine derivative is as low as 66%. However, the method of Reaction Scheme 1 is not suitable for mass production owing to its severe reaction condition and low yield.
In addition, Korean Patent No. 10-0269048 and EP 0871625 disclose that the pyrimidine derivative is prepared via the method of Reaction Scheme 1 in the presence of a solvent, and the yield of the target product is 90%. However, in this case, there are problems in that phosphoryl chloride used in an excessive amount is hardly removed and the resultant product has low purity.
Figure US20130005973A1-20130103-C00003
Meanwhile, Korean Unexamined Patent Publication No. 10-2009-0014468 discloses a process for preparing substituted thiopyrimidine derivatives by introducing a thiol group to a pyrimidine derivative, as shown in the following Reaction Scheme 2, to increase the purity of the pyrimidine derivative.
Figure US20130005973A1-20130103-C00004
However, the above process is not amenable to industrial mass production due to the increased number of steps as compared to Reaction Scheme 1, the use of expensive thiol derivatives, and the bad odor generated during the step using thiol. Next, Korean Patent No. 1993-0011039 and EP 0440372 disclose processes for carrying out a coupling reaction between pyrimidine derivatives and ketone derivatives. Herein, as shown in the following Reaction Scheme 3, LDA (lithium diisopropylamide), a strong base, or sodium bis(trimethylsilyl)amide is used to perform the coupling reaction.
Figure US20130005973A1-20130103-C00005
However, the above methods are problematic in that they use highly explosive strong bases and require equipment capable of cryogenic reaction. Above all, the methods provide very low yield due to the low stereoselectivity and difficulty in separating isomers, and thus are not amenable to mass production.
To overcome the above-mentioned problems, Korean Patent No. 10-0269048 and EP 0871625 disclose a method by which the stereoselectivity is increased through the Reformatsky-type coupling reaction as depicted in the following Reaction Scheme 4, and enantiomeric pairs (2R,3S/2S,3R) are separated in the form of their hydrochloride salts via crystallization, thereby increasing the yield.
Figure US20130005973A1-20130103-C00006
However, the method is problematic in that it results in a relatively low yield of 65% despite a high ratio of the enantiomeric pairs of 9:1 (2R,3S/2S,3R:2R,3R/2S,3S).
The method has another problem related to the removal of halo after the hydrochloride salts are treated with base.
EP 0069442 discloses a method for preparing 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone, one of the main intermediates of Voriconazole, according to the following Reaction Scheme 5.
Figure US20130005973A1-20130103-C00007
However, the above method provides a low yield of 40%.






 








..............................

 Scheme E.

Figure US08263769-20120911-C00007
wherein,

 Example 7 Preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol(voriconazole)
10 g of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol (R)-camsylate obtained in Example 6 was added to a mixture of 50 ml of water and 50 ml of dichloromethane, and a 40% sodium hydroxide solution was slowly added thereto to adjust the pH to 11˜12. The organic layer was separated therefrom and dried over magnesium sulfate, and the organic solvent was removed under a reduced pressure. The resulting solution was crystallized with 18 ml of isopropanol, cooled to 0° C., stirred for 2 hours, and dried to obtain the white title compound (5.56 g, yield: 93%).
m.p=134
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 9.04 (1H), 8.84 (1H), 8.23 (1H), 7.61 (1H), 7.28 (1H), 7.17 (1H), 6.91 (1H), 5.97 (1H), 4.80 (1H), 4.34 (1H), 3.93 (1H), 1.1 (3H)
The optical purity of the compound obtained from HPLC analysis was >99.9%.
Comparative Example Preparation of (2R,3S)/(2S,3R)-(2R,3R)/(2S,3S)-3-(4-chloro-5-fluoropyrimidine-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol hydrochloride
5.29 g of zinc powder treated with 1N HCl and 0.26 g of lead powder were added to 33.5 ml of tetrahydrofuran and stirred, and 3.98 g of iodine dissolved in 10.6 ml of tetrahydrofuran was slowly added thereto for 10 min while heating to 45° C. The resulting mixture was cooled to 2° C., and a solution dissolving 3.53 g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone in 30 ml of tetrahydrofuran, 5 g of 6-(1-bromo-ethyl)-4-chloro-5-fluoropyrimidine and 0.32 g of iodine were slowly added thereto for 10 min. The obtained mixture was heated to 25° C. and reacted for 1 hour.
4.67 g of glacial acetic acid and 12 ml of water were added to the reaction solution, solid metal residue was filtered out, and tetrahydrofuran was removed under a reduced pressure.
The resulting residue was extracted twice with 66 ml of ethyl acetate, and the extract was successively washed with 4.67 g of disodium ethylenediaminetetraacetate dehydrate dissolved in 12 ml of water, and 30 ml of brine. The organic layer was concentrated to 40 ml volume, and 0.86 g of HCl dissolved in 4.3 ml of isopropanol was added thereto at 25° C.
The obtained crystal was filtrated, washed with 10 ml of ethyl acetate, and dried to obtain the title compound as a yellow crystal (2.81 g, yield: 42%).
m.p=126˜130° C.
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.84 (1H), 8.73 (1H), 7.93 (1H), 7.28 (1H), 7.20 (1H), 6.91 (1H), 4.82 (1H), 4.54 (1H), 3.93 (1H), 1.14 (3H)
The enantiomer ratio obtained from HPLC analysis of the reaction solution by using an internal standard material was 10:1, and 14.39% of unknown byproduct was formed. Further, the ratio of (2R,3S)/(2S,3R)- and (2R,3R)/(2S,3S)-enantiomeric pair obtained from HPLC analysis of the crystallized hydrochloride was 94.4%:4.8%.
.........................
 Patent WO2007132354A2


..................
http://www.google.co.in/patents/WO2009024214A1?cl=en


Example 18
(2R.3S)-2-(2.4-Difluorophenvn-3-(5-fluoropyrimidin-4-yl)-1 -d H-1.2.4-triazol-
1-yl)butan-2-ol (voriconazole), compound of Formula (\) To a solution of the racemic material as obtained in example 15 (1.28 g, 3.66 mmol) in acetone (29 ml) was added a solution of (1R)-10-camphorsulfonic acid (0.85 g, 3.66 mmol) in methanol (9.6 ml). The solvents were removed at reduced pressure, and the residue was dissolved in a mixture of acetone (10 ml) and methanol (2 ml). Crystals formed spontaneously after 3 h. Acetone (10 ml) was added, and the mixture was stirred overnight. The solid was isolated by filtration, washed with a small amount of acetone and dried. The solid was dissolved in a mixture of acetone (14 ml) and methanol (4 ml) at reflux. The solution was cooled to rt and stirred for 90 min. Isolation of the precipitate formed by filtration, washing with acetone and drying afforded 0.72 g of the acid addition salt. 0.70 g of the solid material was taken up in dichloromethane (10 ml) and water (10 ml), and the pH was adjusted to 11 by addition of aqueous sodium hydroxide (15% sol.). The layers were separated, and the aqueous layer was extracted with dichloromethane (5 ml). The combined organic layers were washed with water (3 x 10 ml) and brine, and dried (sodium sulfate). Concentration at reduced pressure afforded 0.36 g (28% yield, 56% of the available enantiomer) of voriconazole as a white crystalline solid. Purity, HPLC: 99.8% (RT=4.91 min). Mp. 122.6 0C (Lit. 134 0C). MS, m/z (% rel. int.): 224.0 (27), 350.1 (100), 391.0 (10). 1H NMR (600 MHz, DMSO-d6): δ 9.02 (1H, d, J 3.0 Hz)1 8.83 (1 H1 d, J 1.8 Hz), 8.21 (1 H1 s), 7.59 (1 H1 s), 7.24 (1H1 ddd, J 7.0 Hz, J 9.0 Hz, J 9.0 Hz), 7.16 (1H, ddd, J 2.4 Hz, J 9.0 Hz, J 11.8 Hz), 6.89 (1H, ddd, J 2.4 Hz, J 8.4 Hz, J 8.4 Hz), 5.95 (1 H, s), 4.77 (1 H, d, J 14.4 Hz), 4.31 (1H, d, J 14.4 Hz), 3.90 (1 H, q, J 7.0 Hz), 1.08 (3H1 d, J 7.0 Hz).
Example 19
(2R.3S)-2-(2.4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -d H-1.2.4-triazol-
1 -yl)butan-2-ol (voriconazole), compound of Formula (I) (2R,3S)-2-(2,4-Difluorophenyl)-3-[5-fluoropyrimidin-4-yl]-1-(1 H-1 ,2,4-triazol- 1-yl)butan-2- ol (R)-10-camphorsulfonate (656 g, 1.13 mol) was parted between dichloromethane (3 L) and water (3 L), and the pH of the aqueous phase was slowly adjusted to pH 12.3 with aqueous sodium hydroxide (40% w/v, 130 mL). The phases were separated, and the aqueous layer was extracted with dichloromethane (1 L). The combined organic layers were washed with water (3 x 1.5 L) and filtered. The solvent was changed to isopropanol (1.3 L) via gradual addition/evaporation at reduced pressure. After stirring for 3 h at 20 0C, the temperature was lowered to -5 0C. The mixture was stirred for another 1.5 h, and the product was isolated by suction filtration, washed with isopropanol (0.3 L) and dried at 20 0C and vacuum for 2.5 days. 285 g (72% yield) of the title compound was obtained as a white solid. Purity, HPLC: 99.8%. Optical purity, HPLC: >99.9%. 1H NMR (300 MHz, DMSO-d6): δ 9.05 (1H1 d, J 3.0 Hz), 8.86 (1H1 d, J 1.8 Hz), 8.24 (1H, s), 7.62 (1H, s), 7.24 (2H, m), 6.92 (1H, dt, J 2.1, 8.0 Hz), 5.99 (1H, s), 4.81 (1H1 d, J 14.1 Hz), 4.34 (1H1 d, J 14.4 Hz), 3.93 (1H, q, J 7.2 Hz), 1.11 (3H1 d, J 6.9 Hz). 13C NMR spectrum and IR spectrum for the isolated compound are attached.



 



......................
PAPER
J. Org. Chem., 2013, 78 (22), pp 11396–11403
DOI: 10.1021/jo4019528


..........................
Org. Proc. Res. Dev., 2001, 5 (1), pp 28–36
DOI: 10.1021/op0000879
(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1). ...............to provide the title compound as a white solid (7.6 g, 40% mass yield or 80% of available enantiomer), mp 134 °C
1H NMR (DMSO-d6) δ 1.1 (d, 3H), 3.93 (q, 1H), 4.34 (d, 1H), 4.80 (d, 1H), 5.97 (bs, 1H), 6.91 (ddd, 1H), 7.17 (ddd, 1H), 7.28 (ddd, 1H), 7.61 (s, 1H), 8.23 (s, 1H), 8.84 (s, 1H), 9.04 (s, 1H) ppm.






Cited PatentFiling datePublication dateApplicantTitle
US658659426 Jul 19961 Jul 2003Pfizer, Inc.Preparation of triazoles by organometallic addition to ketones and intermediates therefor
CN1488630A8 Oct 200214 Apr 2004张文更Method for preparing triazole antifungal agent
CN1814597A9 Dec 20059 Aug 2006北京丰德医药科技有限公司New method for preparing voriconazole
EP0440372A124 Jan 19917 Aug 1991Pfizer LimitedTriazole antifungal agents
GB2452049A


Title not available
WO1993007139A11 Oct 199215 Apr 1993Pfizer LtdTriazole antifungal agents
WO1997006160A126 Jul 199620 Feb 1997Michael ButtersPreparation of triazoles by organometallic addition to ketones and intermediates therefor
WO2006065726A213 Dec 200522 Jun 2006Reddys Lab Ltd DrProcess for preparing voriconazole
WO2007013096A126 Jun 20061 Feb 2007Msn Lab LtdImproved process for the preparation of 2r, 3s-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol (voriconazole)
WO2007132354A229 Jan 200722 Nov 2007Medichem SaProcess for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof
WO2009024214A1 *10 Jul 200826 Feb 2009Axellia Pharmaceuticals ApsProcess for the production of voriconazole
WO2009084029A22 Dec 20089 Jul 2009Venkatesh BhingolikarImproved process for the preparation of (2r,3s)-2-(2,4- difluqrophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol
US8575344 *1 Feb 20115 Nov 2013Dongkook Pharmaceutical Co., Ltd.Process for preparing voriconazole by using new intermediates
US20130005973 *1 Feb 20113 Jan 2013Dongkook Pharmaceutical Co., Ltd.Process for preparing voriconazole by using new intermediates
WO2011096697A2 *1 Feb 201111 Aug 2011Dongkook Pharmaceutical Co., Ltd.Process for preparing voriconazole by using new intermediates
US8263769 *4 Aug 200811 Sep 2012Hanmi ScienceProcess for preparing voriconazole
US85753441 Feb 20115 Nov 2013Dongkook Pharmaceutical Co., Ltd.Process for preparing voriconazole by using new intermediates
US20100190983 *4 Aug 200829 Jul 2010Hanmi Pharm, Co., Ltd.Process for preparing voriconazole

WO1997006160A1 *26 Jul 199620 Feb 1997Michael ButtersPreparation of triazoles by organometallic addition to ketones and intermediates therefor
WO2006065726A2 *13 Dec 200522 Jun 2006Reddys Lab Ltd DrProcess for preparing voriconazole
EP0440372A1 *24 Jan 19917 Aug 1991Pfizer LimitedTriazole antifungal agents
Reference
1
Butters et al., "Process Development of Voriconazole: A Novel Broad-Spectrum Triazole Antifungal Agent," Organic Process Research & Development, 2001, vol. 5, pp. 28-36.

References:
Ergosterol biosynthesis inhibitor. Prepn: S. J. Ray, K. Richardson, EP 440372; eidem, US 5278175 (1991, 1994 both to Pfizer); R. P. Dickinson et al., Bioorg. Med. Chem. Lett. 6, 2031 (1996).
Mechanism of action: H. Sanati et al.,Antimicrob. Agents Chemother. 41, 2492 (1997). In vitro antifungal spectrum: F. Marco et al., ibid. 42, 161 (1998).
HPLC determn in plasma: R. Gage, D. A. Stopher, J. Pharm. Biomed. Anal. 17, 1449 (1998).
Review of pharmacology and clinical development: P. E. Verweij et al., Curr. Opin. Anti-Infect. Invest. Drugs 1, 361-372 (1999); J. A. Sabo, S. M. Abdel-Rahman, Ann. Pharmacother. 34, 1032-1043 (2000).
Clinical pharmacokinetics: L. Purkins et al., Antimicrob. Agents Chemother. 46, 2546 (2002).
Clinical comparison with amphotericin B: T. J. Walsh et al., N. Engl. J. Med. 346, 225 (2002).





Voriconazole
Voriconazole structure.svg
Voriconazole ball-and-stick.png
Systematic (IUPAC) name
(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
Clinical data
Trade names VFEND
AHFS/Drugs.com monograph
MedlinePlus a605022
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • D
Legal status
  • ℞ (Prescription only)
Routes of
administration		 IV, oral
Pharmacokinetic data
Bioavailability 96%
Protein binding 58%
Metabolism Hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, CYP3A4
Biological half-life Dose-dependent
Identifiers
CAS Registry Number 137234-62-9 Yes
ATC code J02AC03
PubChem CID: 71616
DrugBank DB00582 Yes
ChemSpider 64684 Yes
UNII JFU09I87TR Yes
KEGG D00578 Yes
ChEBI CHEBI:10023 Yes
ChEMBL CHEMBL638 Yes
Chemical data
Formula C16H14F3N5O
Molecular mass 349.311 g/mol




 
 11
 POSACONAZOLE
......
Posaconazole.svg


Posaconazole  泊沙康唑 ,  بوساكونازول , Позаконазол
Sch-56592
4-[4-[4-[4-[[(5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one
  1. Noxafil
  2. SCH 56592
U.S. Patents 5,661,151; 5,703,079; and 6,958,337.


Therap-Cat: Antifungal.

CAS 171228-49-2

Molecular Formula: C37H42F2N8O4

Molecular Weight: 700.78

CAS Name: 2,5-Anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol
Additional Names: (3R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl]-2-[1(S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-1,2,4-triazol-3-one

Syn..........Dominic De Souza, "PREPARATION OF POSACONAZOLE INTERMEDIATES." U.S. Patent US20130203994, issued August 08, 2013.
Percent Composition: C 63.41%, H 6.04%, F 5.42%, N 15.99%, O 9.13%

  1. Melting Point


  • 170-172 deg C
    O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365

    1. In water, 0.027 mg/L at 25 deg C (est)
      US EPA; Estimation Program Interface (EPI) Suite. Ver.3.12. Nov 30, 2004. Available from, as of Dec 19, 2005:http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
    US5661151   EXP Jul 19, 2019  PRODUCT PATENT
    US 5703079  EXP Aug 26, 2014
    US8410077 EXPMar 13, 2029
    US9023790 EXPJul 4, 2031
    US 6958337 EXP Oct 5, 2018
    US 8263600 EXPApr 1, 2022
    Posaconazole is a triazole antifungal drug[1][2] marketed in the United States, the European Union, and in other countries by Schering-Plough under the trade name Noxafil. In Canada, posaconazole is marketed by Schering-Plough under the trade name Posanol.
    Noxafil.png

    Pharmacology

    Mode of action

    Posaconazole works by disrupting the close packing of acyl chains of phospholipids, impairing the functions of certain membrane-bound enzyme systems such as ATPase and enzymes of the electron transport system, thus inhibiting growth of the fungi. It does this by blocking the synthesis of ergosterol by inhibiting of the enzymelanosterol 14α-demethylase and accumulation of methylated sterol precursors. Posaconazole is significantly more potent at inhibiting 14-alpha demethylase than itraconazole.[3][4][5]

    Microbiology

    Posaconazole is active against the following microorganisms:[3][6]

    Pharmacokinetics

    Posaconazole is absorbed within three to five hours. It is predominately eliminated through the liver, and has a half life of about 35 hours. Oral administration of posaconazole taken with a high-fat meal exceeds 90% bioavailabilityand increases the concentration by four times compared to fasting state.[6][7]

    Clinical use

    It is used to treat invasive infections by Candida species,[8] Mucor, and Aspergillus species[9] in severelyimmunocompromised patients.
    Clinical evidence for its utility in treatment of invasive disease caused by Fusarium species (fusariosis) is limited.[10]
    Two studies suggest posaconazole may be superior to other triazoles, such as fluconazole or itraconazole, in the prevention of invasive fungal infections, although it may cause more serious side effects.[11][12]
    There is also some indication that posaconazole may be the most effective treatment for both chronic and acute Chagas disease, showing much better efficacy than benznidazole.[13] Schering-Plough is currently recruiting participants for a phase 2 clinical trial in Argentina to test its efficacy against asymptomatic, chronic Chagas.[14]

    SYNTHESIS






    ................
    http://www.google.com/patents/WO2013042138A2?cl=en
    HPLC Method of Analysis for Posaconazole:
    Posaconazole is analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Grace Alltima CI 8, 150 x 4.6mm 3μηι or equivalent; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Column Temperature: 28°C; Injection volume: 10
    Figure imgf000038_0001
    Run time: 60 min; Diluent: Acetonitrile: water (50:50 v/v); Needle wash: Acetonitrile: water (50:50 v/v); Elution: Gradient; Mobile phase-A: Buffer Acetonitrile (90: 10) v/v; Mobile phase- B: Acetonitrile: water (90:10) v/v; Buffer: 1.74 grams of potassium hydrogen phosphate in 1000 ml of water. Adjust pH to 6.5 with diluted orthophosphoric acid and filtered through 0.45μηι Nylon membrane filter paper and sonicate to degas it. PSD method of analysis for Posaconazole:
    The particle size distribution of posaconazole compound of formual-1 is measured using the following conditions:
    Instrument: Malvern Master sizer 2000; Measuring range: 0.02 to 2000 μπι; Wet sample: Hydro 2000S; Dispersant: Water; Absorption Index: 0; Refractive Index of water: 1.330; Refractive Index of particle: 1.500; Stirrer speed: 2500 rpm; Obscuration range: 10-20%; Sensitivity: Normal; Measurement time: 12 seconds; Background time: 12 seconds; Internal sonication: 3 minutes; (Tip displacement-70%); Measurement repeat: 3 times at zero second interval.
    HPLC Method of Analysis for Benzylated Posaconazole:
    Benzylated posaconazole is analyzed by HPLC using the following conditions:
    Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: X-bridge C18, 50X 4.6mm, 3.5um (or) equivalent; Flow rate: 0.8 ml/min; Wavelength: 210 nm; Column Temperature: 40°C; Injection volume: 5 μΐ,; Run time: 35 min; Diluent: Water: Acetonitrile (40:60) v/v; Needle wash: Water: Acetonitrile (40:60) v/v; Elution: Gradient; Mobile phase-A: Buffer Acetonitrile (90: 10) v/v; Mobile phase-B: Acetonitrile: water (90:10) v/v; Buffer: 1.74 grams of potassium hydrogen phosphate dibasic (anhydrous) in 1000 ml of Milli-Q- Water. Adjust its pH to 6.5 with diluted orthophosphoric acid and filtered through 0.22μπι Nylon membrane filter paper and sonicate to degas it. PXRD analysis of crystalline triazole antifungal compound of formula- 1 was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
    RS/OVI analysis of amorphous posaconazole is carried out on Agilent GC-6850 series-2 with Flame Ionization detector, column AP vac, flow 2 psi and load is 1 μΐ, detector temperature is 260°C and carrier gas is helium.
    The process of the present invention is schematically represented as below:
    Scheme-I

    Figure imgf000040_0001
    ormiia- ormua-
    Scheme-II:

    Figure imgf000040_0002
    Formula-16 Scheme-Ill:
    HO N N- NH,
    Formula-18

    Figure imgf000041_0001
    Pure POSACONAZOLE
    Patent WO2013042138A2
    1. An improved process for the preparation of (3S,5R)-5-(2,4-difluorophi
    (iodomethyl)tetrahydrofuran-3-ca boxylic acid compound of formula-7,
    Figure imgf000061_0001
    Forrnula-7
    comprising of the following steps:
    a) Reacting 4-(2,4-difluorophen ent-4-enoic acid compound of formula-2
    Figure imgf000061_0002
    Formula-2
    with (R)-4-phenyloxazolidin-2-one compound of formula-3
    Figure imgf000061_0003
    Formula-3
    in presence of a suitable activating agent and a suitable base in a suitable solvent to provide (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,
    Figure imgf000061_0004
    Formula-4
    b) hydroxymethylating the compound of formula-4 with 1,3,5-trioxane in presence of a base and a catalyst in a suitable solvent to provide (R)-3-((S)-4-(2,4- difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5,
    Figure imgf000062_0001
    Formula-5
    c) cyclizing the compound of formula-5 in-situ in presence of iodine and a suitable base in a suitable solvent to provide (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5- (iodomethyl)tetrahydrofuran-3 -carbonyl)-4-phenyloxazolidin-2-one compound of formula-6,
    Figure imgf000062_0002
    Formula-6
    d) hydrolyzing the compound of formula-6 in presence of a suitable aqueous base and hydrogen peroxide in a suitable solvent to provide (3S,5R)-5-(2,4- difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7. 
     formula-7,
    Figure imgf000064_0001
    Formula-7
    b) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-yl)methanol compound of formula-8,
    Figure imgf000064_0002
    Formula-8

     Example-16: Preparation of Posaconazole (Formula- 1)
    5N hydrochloric acid (72 ml) and 10% Pd-C (10 g) were added to a solution of 4- (4_(4-(4-(((3Κ,5Κ)-5-(( i H- 1 ,2,4-triazol- 1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydro furan-3-yl)methoxy)phenyl)piperazin-l-yl)phenyl)-l-((2S,3R)-2-(benzyloxy)pentan-3- yl)-lH-l,2,4-triazol-5(4H)-one compound of formula-21 (42 g) in methanol (420 ml). The reaction mixture was hydrogenated for 5 hours under a hydrogen gas pressure of 4-5 kg/cm2 at 50°. After completion of reaction, the catalyst was filtered off and washed with methanol. pH of the filtrate was adjusted to ~7.0 using 4N sodium hydroxide. Water was added to the reaction mixture and stirred for 2 hours at 25-35°C. Filtered the separated solid and washed with water. The obtained solid was dissolved in acetone (320 ml)and stirred at reflux temperature for 30 minutes. Filtered the undissolved product and added water to the filtrate and stirred the reaction mixture for 4 hours at 25-35°C. Filtered the separated solid and washed with water. Further the solid was recrystallized from isopropyl alcohol to get the title compound. Purity by HPLC: 99.85%; Yield: 75.0%: Chiral purity by HPLC: 99.82%.




    ......................
     Posaconazole, SCH-56592, Noxafil
     
     EP 0736030; JP 1997500658; US 5661151; US 5703079; WO 9517407
    Synthesis of intermediate (XX): The reaction of 2-chloro-2',4'-difluoroacetophenone (I) with sodium acetate and NaI in DMF gives 2-acetoxy-2',4'-difluoroacetophenone (II), which by methylenation with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF yields 2-(2,4-difluorophenyl)-2-propen-1-ol acetate ester (III). The hydrolysis of (III) with KOH in dioxane/water affords the corresponding alcohol (IV), which is regioselectively epoxidized with titanium tetraisopropoxide and L-(+)-diethyl tartrate in dichloromethane to (S)-(-)-2-(2,4-difluorophenyl)oxirane-2-methanol (V). The reaction of (V) with 1,2,4-triazole (VI) in DMF affords (R)-2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol (VII), which is selectively mesylated with methanesulfonyl chloride and triethylamine to the monomesylate (VIII). The cyclization of (VIII) with NaH in DMF gives the oxirane (IX), which is condensed with diethyl malonate (X) by means of NaH in DMSO to yield a mixture of (5R-cis)- and (5R-trans)-5-(2,4-difluorophenyl)-2-oxo-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-carboxylic acid ethyl ester (XI). The reduction of (XI) with NaBH4 and LiCl in ethanol affords (R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1,2,4-triazol-1-yl) pentane-1,4-diol (XII), which is selectively tosylated with tosyl chloride and triethylamine in THF to the bistosylate (XIII). The cyclization of (XIII) by means of NaH in refluxing toluene gives (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol tosylate ester (XIV). The reaction of (XIV) with 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)piperazine (XV) to obtain compound (XVI), and the following reaction sequence (XVI) to (XVII) to (XVIII) to (XIX) to (5R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl-3,4-dihydro-2H-1,2,4-triazol-3-one (XX) has been performed according to J Med Chem 1984, 27: 894-900.

     
     The bromosulfonate (XXI) has been obtained as follows: (S)-Lactic acid methyl ester (XXII) has been protected as its benzyloxymethyl ether (XXIII) according to Tetrahedron Lett 1980, 21: 1035. The reduction of (XXIII) with DIBAL yields the corresponding aldehyde (XXIV), which by a Grignard reaction with ethylmagnesium bromide in THF and chromatographic separation of the diastereoisomers (SiO2, hexane/ethyl acetate) affords 2(S)-(benzyloxymethoxy)-3(R)-pentanol (XXV). Finally, this compound is sulfonated to (XXI) with 4-bromobenzenesulfonyl chloride. Finally, compound (XX) is condensed with 2(S)-(benzyloxymethoxy)-3(R)-pentanol 4-bromobenzenesulfonate ester (XXI) by means of cesium carbonate in DMF, and deprotected with 6N HCl.
     .....................

     WO 9633178
     
     A new synthesis of Sch-56592 has been described: The reaction of (S)-ethyl lactate (I) with pyrrolidine (II) gives 1-[(S)-lactoyl]pyrrolidine (III), which is benzylated as usual with benzyl chloride yielding the benzyl ether (IV). The reaction of (IV) with ethylmagnesium bromide in THF affords 2(S)-benzyloxy-3-pentanone (V), which is reduced with LiBH4 in dimethoxyethane giving 2(S)-benzyloxy-3(RS)-pentanol (VI). The reaction of (VI) with 4-chlorobenzenesulfonyl chloride (VII) yields the corresponding sulfonate (VIII), which is treated with hydrazine in ethanol to afford a diastereomeric mixture of hydrazines that is resolved with L-dibenzoyltartaric acid giving the (S,S)-enantiomer (IX). The formylation of (IX) with refluxing ethyl formate yields the chiral formyl hydrazide (X), which is cyclized with N-[4-[4-[4-(trimethylsilyloxy)phenyl]piperazin-1-yl]phenyl]carbamic acid phenyl ester (XI) affording the triazolone (XII). Finally, this compound is condensed with the chiral tetrahydrofuran derivative (XIII) by means of NaOH in DMSO, and debenzylated by hydrogenation with H2 over Pd/C in formic acid



    .....................
    \35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995,Abst F83.

     

     2) The 2-(2,4-difluorophenyl)-2-propen-1-ol (IV) is converted into the corresponding propenyl bromide (XXVI), which is condensed with diethyl malonate (X) to afford the malonyl derivative (XXVII). The reduction of (XXVII) with NaBH4 and LiCl yields the 1,3-propanediol derivative (XXVIII), which is enantioselectively acetylated with vinyl acetate and Novozyme 435 in acetonitrile yielding the isomeric (S)-monoacetate (XXIX). The cyclization of (XXIX) with iodine and NaHCO3 in acetonitrile affords (5R-cis)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-methanol acetate ester (XXX), which is condensed with sodium 1,2,4-triazole (XXXI) to give (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol acetate ester (XXXII). The hydrolysis of (XXXII) with NaOH yields the corresponding methanol (XXXIII), which is finally tosylated to the tosyl ester (XIV), already obtained previously.
    .........................
     35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995,Abst F61

     

     3) The Friedel Crafts condensation of m-difluorobenzene (XXXIV) with succinic anhydride (XXXV) gives 4-(2,4-difluorophenyl)-4-oxobutyric acid (XXXVI), which is converted by a Wittig reaction into 4-(2,4-difluorophenyl)-4-pentenoic acid (XXXVII) and subsequently into its acyl chloride (XXXVIII). The condensation of (XXXVIII) with 4(R)-benzyloxazolidin-2-one (XXXIX) gives the acyl oxazolidinone (XL), which is regioselectively hydroxymethylated with 1,3,5-trioxane and TiCl4 to afford 4(R)-benzyl-3-[4-(2,4-difluorophenyl)-3(S)-(hydroxymethyl)-4-pentenoyl] oxazolidin-2-one (XLI). The cyclization of (XLI) with iodine and pyridine yields the tetrahydrofuran derivative (XLII), which is reduced with LiBH4 to (5R-cis)-5-(2,4-difluoromethyl)-5-(iodomethyl)tetrahydrofuran-3-methanol (XLIII). Finally, this compound is condensed with sodium 1,2,4-triazole (XXXI) to afford (5R-cis)-5-(2,4-difluoromethyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol (XXXIII), already obtained in Scheme 22656201c.


    .................
     J Label Compd Radiopharm 1998,41(8),731
     

     The synthesis of [3H]-SCH-51048 has been described: The tritiation of phenol (I) with tritiated heptafluorobutyric acid at 115 C gives the polytritiated intermediate (II), which is then condensed with the chiral tosylate (III) by means of NaOH in DMSO affording labeled SCH-51048.



     ......................
     

     The synthesis of [14C]-SCH-56592 has been described: The cyclization of semicarbazide (I) with [14C]-formamidine (II) in hot 2-methoxyethanol gives the triazolone (III), which is condensed with the sulfonate (IV) by means of Cs2CO3 in hot DMF to yield the alkylated triazolone (V). Finally, this compound is deprotected by hydrogenation with formic acid over Pd/C in hot methanol to afford labeled SCH-56592.
    ..................

     Tetrahedron Lett 2002,43(18),3359





     The condensation of 4-chlorophenylsulfonate (I) with 4-bromophenol (II) by means of K2CO3 in hot DMF gives the aryl ether (III), which is condensed with piperazine (IV) by means of Pdo to yield the monosubstituted piperazine (V). Finally, this compound is condensed with the 4-bromophenyltriazolone (VI) by means of K2CO3 in hot DMSO to afford the target disubstituted piperazine


     


     Alternatively, the condensation of with the 4-bromophenyltriazolone (VI) with piperazine (IV) by means of Pd2(dba)3, BINAP and t-BuONa in hot toluene gives the monosubstituted piperazine (VII), which is then condensed with the already reported aryl ether (III) by means of Pd2(dba)3, BINAP and t-BuONa in hot toluene, and debenzylated with Pd/C and formic acid to afford the target disubstituted piperazine.



     
     The intermediate 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) has been obtained by several related ways: 1.- The condensation of 4-bromonitrobenzene (I) with piperazine (II) gives 1-(4-nitrophenyl)piperazine (III), which is condensed with 4-bromoanisole (IV) by means of Pdo to yield 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V). Alternatively, (V) can also be obtained by condensation of (III) with 4-methoxyphenylboronic acid (VI) by means of Cu(OAc)2 in DMSO. The demethylation of (V) with HBr yields 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (VII), which is finally reduced with H2 over Pd/C to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). 2.- The condensation of piperazine (II) with 4-bromoanisole (IV) by means of Pdo gives 1-(4-methoxyphenyl)piperazine (IX), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in hot DMSO to yield intermediate 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), already reported. 3.- The condensation of piperazine (II) with 4-(benzyloxy)phenyl bromide (X) by means of Pdo gives 1-(4-benzyloxyphenyl)piperazine (XI), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and TBAI in hot DMSO to yield 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII). The nitro group of (XII) is reduced by means of H2 (50 psi) over Pd/C in wet THF at 50? C to afford 4-[4-(4-benzyloxyphenyl)piperazin-1-yl]aniline (XIII), which is finally debenzylated with H2 (80 psi) over Pd/C in wet THF at 70? C or other drastic conditions to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). Alternatively, 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII) can also be reduced directly to the target intermediate (VIII) with H2 over Pd/C under a variety of drastic conditions.
    Literature References: 

     Orally active triazole antifungal. Prepn: A. K. Saksena et al., WO 9517407; eidem, US 5661151 (1995, 1997 both to Schering); eidem, Tetrahedron Lett. 37, 5657 (1996). 

     Comparative antifungal spectrum: A. Cacciapuoti et al., Antimicrob. Agents Chemother. 44, 2017 (2000). Pharmacokinetics, safety and tolerability: R. Courtney et al., ibid. 47, 2788 (2003). 

     HPLC determn in serum: H. Kim et al., J. Chromatogr. B 738, 93 (2000). 

     Review of development: A. K. Saksena et al. inAnti-Infectives: Recent Advances in Chemistry and Structure Activity Relationships (Royal Soc. Chem., Cambridge, 1997) pp 180-199; and clinical efficacy in fungal infections: R. Herbrecht, Int. J. Clin. Pract. 58, 612-624 (2004).

    References

    1. Jump up^ Schiller DS, Fung HB (September 2007)."Posaconazole: an extended-spectrum triazole antifungal agent". Clin Ther 29 (9): 1862–86.doi:10.1016/j.clinthera.2007.09.015.PMID 18035188.
    2. Jump up^ Rachwalski EJ, Wieczorkiewicz JT, Scheetz MH (October 2008). "Posaconazole: an oral triazole with an extended spectrum of activity". Ann Pharmacother 42(10): 1429–38. doi:10.1345/aph.1L005.PMID 18713852.
    3. ^ Jump up to:a b Brunton L, Lazo J, Parker K. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. San Francisco: McGraw-Hill; 2006. ISBN 978-0-07-142280-2
    4. Jump up^ "Clinical Pharmacology Pasoconazole". Retrieved18 February 2010.
    5. Jump up^ "Daily Med, Product Information Noxafil". Retrieved18 February 2010.
    6. ^ Jump up to:a b Dodds Ashley, Elizabeth; Perfect, John (October 13, 2009). "Pharmacology of azoles". Retrieved18 February 2010.
    7. Jump up^ "Drugs at FDA: Noxafil" (PDF). Retrieved18 February 2010.
    8. Jump up^ Li X, Brown N, Chau AS et al. (January 2004)."Changes in susceptibility to posaconazole in clinical isolates of Candida albicans". J. Antimicrob. Chemother. 53 (1): 74–80. doi:10.1093/jac/dkh027.PMID 14657086.
    9. Jump up^ Walsh TJ, Raad I, Patterson TF et al. (January 2007)."Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial".Clin. Infect. Dis. 44 (1): 2–12. doi:10.1086/508774.PMID 17143808.
    10. Raad I, Hachem R, Herbrecht R et al. (2006)."Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions". Clin Infect Dis 42(10): 1398–1403.
    11. Cornely O, Maertens J, Winston D, Perfect J, Ullmann A, Walsh T, Helfgott D, Holowiecki J, Stockelberg D, Goh Y, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D (2007). "Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia". N Engl J Med356 (4): 348–59. doi:10.1056/NEJMoa061094.PMID 17251531.
    12.  Ullmann A, Lipton J, Vesole D, Chandrasekar P, Langston A, Tarantolo S, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, Patino H, Durrant S (2007). "Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease". N Engl J Med 356 (4): 335–47. doi:10.1056/NEJMoa061098.PMID 17251530.
    13. J "Am J Trop Med Hyg April 2010 vol. 82 no. 4"
    14.  "A Study of the Use of Oral Posaconazole (POS) in the Treatment of Asymptomatic Chronic Chagas Disease (P05267 AM1) (STOP CHAGAS)"

    Noxafil is an azole antifungal agent available as concentrated solution to be diluted before intravenous administration, delayed-release tablet, or suspension for oral administration.
    Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:
    Posaconazole is a white powder with a low aqueous solubility.
    Noxafil® (posaconazole) Structural Formula Illustration
    Noxafil injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.003 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.
    Noxafil delayed-release tablet is a yellow, coated, oblong tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, Macrogol/PEG 3350, titanium dioxide, talc, and iron oxide yellow).


    Noxafil oral suspension is a white, cherry-flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water.
    Posaconazole
    Posaconazole.svg
    Posaconazole3d.png
    Systematic (IUPAC) name
    4-(4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-hydroxypentan-3-yl)-1,2,4-triazol-3-one
    Clinical data
    Trade namesNoxafil, Posanol
    AHFS/Drugs.commonograph
    MedlinePlusa607036
    Licence dataEMA:Link, US FDA:link
    Pregnancy
    category
    • AU: B3
    • US: C (Risk not ruled out)
    Legal status
    Routes of
    administration    		Oral
    Pharmacokinetic data
    BioavailabilityHigh
    Protein binding98 to 99%
    MetabolismHepatic glucuronidation
    Biological half-life16 to 31 hours
    ExcretionFecal (77%) and renal (14%)
    Identifiers
    CAS Registry Number171228-49-2 Yes
    ATC codeJ02AC04
    PubChemCID: 147912
    DrugBankDB01263 Yes
    ChemSpider130409 Yes
    UNII6TK1G07BHZ Yes
    KEGGD02555 Yes
    ChEBICHEBI:64355 
    ChEMBLCHEMBL1397 
    Synonyms4-{4-[4-(4-{[(5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-1-[(2S,3S)-2-hydroxypentan-3-yl]-4,5-dihydro-1H-1,2,4-triazol-5-one
    Chemical data
    FormulaC37H42F2N8O4
    Molecular mass700.778 g/mol




    1H NMR PREDICT




    13C NMR PREDICT



    COSY PREDICT









    CN101824009A *May 27, 2010Sep 8, 2010北京德众万全药物技术开发有限公司Simple preparation method for posaconazole and piperazine intermediate thereof

    Citing PatentFiling datePublication dateApplicantTitle
    WO2015011224A1 *Jul 24, 2014Jan 29, 2015Sandoz AgImproved process for the preparation of crystalline form iv of posaconazole










    12




    Figure




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