EFINACONAZOLE

EFINACONAZOLE

 
Efinaconazole
(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
(2R, 3R) -2 - (2,4 - difluorophenyl) -3 - (4 - methylene-piperidin-1 - yl) -1 - (1H-1, 2,4 - triazol-1 - yl) butan-2 - manufacture ol (KP-103)
Efinaconazole is a triazole antifungal. It is approved for use in Canada as 10% topical solution for the treatment of onychomycosis (fungal infection of the nail).^[1][2] Efinaconazole acts as a 14α-demethylase inhibitor.^[3]

Identifiers
CAS number	164650-44-6
PubChem	CID 489181
ChemSpider	428538
Chemical data
Formula	C18H22F2N4O
Mol. mass	348.39 g/mol

SEE AT

PATENT

http://www.google.com/patents/WO2012029836A1?cl=en

Method for producing butanol derivatives - 1 - 2 - triazole Is a (compound described in Example 1 of Patent Document 1) a compound of formula 1 to be effective against fungal diseases of humans and animals are known, the present invention, (2R, 3R) - 2 - (2,4 - difluorophenyl) -3 - (4 - methylene piperidin-1 - yl) -1 - (1H-1, 2,4 - triazol-1 - yl) butan-2 - (generic name ol ( The present invention relates to preparation of their salts that Fina et Kona zole (Efinaconazole)), hereinafter abbreviated as "KP-103" or even) in: INN).
Example 1
(2R, 3R) -2 - (2,4 - difluorophenyl) -3 - (4 - methylene-piperidin-1 - yl) -1 - (1H-1, 2,4 - triazol-1 - yl) butan-2 - manufacture ol (KP-103)


Was stirred while addition of acetonitrile 80mL, lithium hydroxide 2.859g methylene piperidine hydrobromide (4-MP · HBr) 21.26g and (119.4mmol) and (119.4mmol) - 4 obtained in Production Example 1. Then, (2R, 3S) -2 - (2,4 - difluorophenyl) -3 - methyl -2 - [(1H-1, 2,4 - triazol-1 - yl) methyl] oxirane and 20g (79.6mmol) was added, and the mixture was heated under reflux for 14 hours at (external temperature 100 ℃) oil bath. After completion of the reaction, to precipitate the crystals by the addition of ethanol and distilled water to the reaction solution. Thereafter, the crystals were filtered, washed with ethanol / water mixture 40mL, and naturally dried at room temperature for 12 hours and dried under reduced pressure at 40 ℃, KP-103 24.2g light yellow 87.3% (yield, HPLC purity 95.3 % I got).
¹ H-NMR (500MHz, CDCl ₃₎
δ: 0.96 (3H, dd, J = 2.68, 7.08 Hz), 2.13-2.26 (4H, m), 2.35 (2H, br), 2.70 (2H, br) ,2.90-2 .94 (1H, q, J = 7.08 Hz), 4.64 (2H, s), 4.82 (1H, dd, J = 0.73, 14.39 Hz), 4.87 (1H, dd, J = 0.73, 14.39 Hz), 5.45 (1H, s), 6.72-6.81 (2H , m), 7.51 (1H, dt, J = 6.59, 9.03 Hz), 7.78 (1H, s),
8.02 (1H, s).
FAB-MS m / z: 349 [M ⁺ H] +
:86-89 ℃ melting point
Optical rotation: [α] _D ²⁵ -87 ~ -91 ° (C = 1.0, methanol)




“Drugs at FDA: JUBLIA”. Retrieved 26 June 2014.

NDA Appl No		RLD	Active Ingredient	Dosage Form; Route	Strength	Proprietary Name	Applicant
N203567		Yes	EFINACONAZOLE	SOLUTION; TOPICAL	10%	JUBLIA	DOW PHARM

JUNE6 2014 APPROVED

Patent Data

Appl No	Prod No	US Patent No	Patent Expiration	Drug Substance Claim	Drug Product Claim	Patent Use Code
N203567	001	7214506	Oct 5, 2021			U – 281
N203567	001	8039494	Jul 8, 2030			U – 281
N203567	001	8486978	Oct 24, 2030		Y

Exclusivity Data

Appl No	Prod No	Exclusivity Code	Exclusivity Expiration
N203567	001	NCE	Jun 6, 2019

Efinaconazole is a triazole antifungal. It is approved for use in Canada as 10% topical solution for the treatment of onychomycosis (fungal infection of the nail).^[1][2] Efinaconazole acts as a 14α-demethylase inhibitor.^[3]



UPDATED

Efinaconazole

(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)-butane-2-ol

EFINACONAZOLE,

KP-103,

cas 164650-44-6, Efinaconazole [INN], UNII-J82SB7FXWB,  AC1LAJ21, Efinaconazole [USAN:INN],

• Efinaconazole
• Jublia
• KP-103
• UNII-J82SB7FXWB

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol

Molecular Formula: C18H22F2N4O   Molecular Weight: 348.390286

efinaconazole

 

1H NMR PREDICT

………………………………………
 13C NMR PREDICT

 COSY PREDICT

HMBC PREDICT

...............................
 ELABORATION

1H NMR PREDICT

13C NMR

PATENT

http://www.google.com/patents/US20130150586

Example 1Production of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (KP-103)21.26 g (119.4 mmol) of the 4-methylenepiperidine hydrobromide (4-MP.HBr) obtained in Production 1 and 2.859 g (119.4 mmol) of lithium hydroxide were added to 80 mL of acetonitrile and stirred for a while. Thereafter, 20 g (79.6 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane was added and the mixture was heated under reflux in an oil bath (external temperature: 100° C.) for 14 hours. After the reaction completed, ethanol and distilled water were added to the reaction mixture, whereupon a crystal was precipitated. Thereafter, the crystal was filtered off, washed with 40 mL of an ethanol/water mixture, dried with air at room temperature and further dried under reduced pressure at 40° C. for 12 hours to give a pale yellow crystal of KP-103 in an amount of 24.2 g (yield, 87.3%; purity on HPLC, 95.3%).

1H-NMR (500 MHz, CDCl3)δ: 0.96 (3H, dd, J=2.68, 7.08 Hz), 2.13-2.26 (4H, m), 2.35 (2H, br), 2.70 (2H, br), 2.90-2.94 (1H, q, J=7.08 Hz), 4.64 (2H, s), 4.82 (1H, dd, J=0.73, 14.39 Hz), 4.87 (1H, dd, J=0.73, 14.39 Hz), 5.45 (1H, s), 6.72-6.81 (2H, m), 7.51 (1H, dt, J=6.59, 9.03 Hz), 7.78 (1H, s), 8.02 (1H, s).

FAB-MS m/z: 349 [M+H]+

melting point: 86-89° C.

optical rotation: [α]D 25 −87 to −91° (C=1.0, methanol)

………………………………….

Journal of Organic Chemistry, 2014 ,  vol. 79,   7  pg. 3272 – 3278

http://pubs.acs.org/doi/abs/10.1021/jo500369y

http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf

A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.

Scheme 3. Synthesis of Efinaconazole (Jublia)

(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Efinaconazole)

To a solution of 1 (54.2 mg, 0.216 mmol) in EtOH (217 μL) was added 4-methylenepiperidine (147 mg, 1.51 mmol), ……………………deleted………………. see original…………….. was purified using silica gel column chromatography (CHCl3/MeOH = 10:1) to give 67.6 mg ofefinaconazole (90% yield) as a colorless amorphous solid.

[α]D20 −87.8 (c 1.12, CHCl3);

1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.76 (s, 1H), 7.51–7.45 (m, 1H), 6.78–6.68 (m, 2H), 5.50 (brs, 1H), 4.85 (d,J = 14.4 Hz, 1H), 4.78 (d, J = 14.4 Hz, 1H), 4.61 (s, 2H), 2.88 (q, J = 6.9 Hz, 1H), 2.66 (br s, 2H), 2.32 (br s, 2H), 2.21–2.17 (m, 4H), 0.93 (dd, J = 6.9, 2.1 Hz, 3H);

13C NMR (150 MHz, CDCl3) δ 162.5 (dd, J = 250, 13 Hz), 158.5 (dd, J = 246, 12 Hz), 151.3, 145.9, 144.4, 130.6 (dd, J = 8.7, 5.8 Hz), 124.7 (dd, J= 14, 3.6 Hz), 111.4 (dd, J = 20, 2.9 Hz), 108.1, 104.1 (dd, J = 28, 25 Hz), 77.7 (d, J = 5.8 Hz), 64.4, 55.9 (d, J = 8.7 Hz), 52.4, 35.2, 7.63 (d, J = 2.9 Hz);

19F NMR (376 MHz, CDCl3) δ −105.8, −110.7;

IR (CHCl3, cm–1) ν 3423, 3073, 2979, 2939, 2899, 2810, 1615, 1498, 1418, 1273, 1138;

HRMS (ESI-TOF) calcd for C18H23ON4F2 [M + H]+ m/z 349.1834, found 349.1828.

http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf

……………

SYN
http://newdrugapprovals.org/2014/06/10/valeant-pharmaceuticals-announces-fda-approval-of-jublia-for-the-treatment-of-onychomycosis/


updated
1H NMR



get clear pic at........http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf

13C NMR

get clear pic at........http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf


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