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Valeant Pharmaceuticals Announces FDA Approval Of Jublia, Efinaconazole for the Treatment of Onychomycosis

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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

cas 164650-44-6

cas of 4-​methylbenzenesulfona​te (1:1)164650-61-7

Butanedioic acid, 2-​hydroxy-​, (2S)​-​, compd with efinaconazole……..1648711-85-6

NMR PREDICT…….SEEhttp://orgspectroscopyint.blogspot.in/2014/06/efinaconazole.html

1H NMR

Displaying image001.png

13 C NMR
Displaying image002.png
1H NMR PREDICT

1H NMR PREDICT(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol NMR spectra analysis, Chemical CAS NO. 164650-44-6 NMR spectral analysis, (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol H-NMR spectrum

………………………………………
13C NMR PREDICT
(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol NMR spectra analysis, Chemical CAS NO. 164650-44-6 NMR spectral analysis, (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol C-NMR spectrum…………………..
COSY

HSQC
………………………….SEE MORE SPECTROSCOPY AT http://orgspectroscopyint.blogspot.in/2014/06/efinaconazole.html

“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]

 

Systematic (IUPAC) name
(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
Clinical data
Trade names Jublia
Licence data US FDA:link
Legal status
Routes Topical
Identifiers
CAS number 164650-44-6
ATC code None
PubChem CID 489181
ChemSpider 428538
Chemical data
Formula C18H22F2N4O 
Mol. mass 348.39 g/mol

http://www.drugs.com/newdrugs/valeant-pharmaceuticals-announces-fda-approval-jublia-onychomycosis-4046.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+June+9%2C+2014

SEE AT

LAVAL, Quebec, June 9, 2014 /PRNewswire/ — Valeant Pharmaceuticals International, Inc. (NYSE: VRX) (TSX: VRX) today announced that that its wholly owned subsidiary, Valeant Pharmaceuticals North America LLC, received notice that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for Jublia® (efinaconazole 10% topical solution), the first topical triazole approved for the treatment of onychomycosis of the toenails

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
Chemical structure for EFINACONAZOLEefinaconazole
 
……………………………….
PAPER
Chemical and Pharmaceutical Bulletin, 1999 ,  vol. 47,  10  pg. 1417 – 1425
2-Aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives I were prepared by ring-opening reaction of epoxides II with excess amine, and their antifungal activities were evaluated as topical agents. Azolyl-cyclic amine derivatives with a methylene group showed extremely strong activity with a broad spectrum in vitro. In general, anti-Trichophyton mentagrophytes activities of most of the topical antifungal agents are substantially reduced by addition of keratin (a major constituent of the keratinized tissue).
However, the triazole derivative (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylenepiperidino)-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol ((-)-40, KP-103) showed very little deactivation by addition of keratin. This biological characteristic of triazole derivative (-)-40 resulted in excellent therapeutic efficacy on dermatophytosis superior to that of the corresponding imidazole derivative ((-)-41).
………………………………………
PATENT
Figure US20130150586A1-20130613-C00002

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
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.
Figure
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 of efinaconazole (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.
…………………………………..
PATENT

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).

Figure JPOXMLDOC01-appb-C000001

The method for obtaining the amino alcohol by ring-opening addition reaction of the amine to the epoxide, in general, using a large excess of amine, and is performed for a long time at a high temperature. In the conventional method, in order to use the amine of the large excess of byproducts is large and requires a recovery step of an amine, also in terms of production costs, it is desirable as a production method on an industrial scale if the amine is expensive no. In order to increase the reactivity of the reaction, the reaction using a Lewis acid have been proposed, also, difficult to use industrially Lewis acid to be used is unstable or expensive, perchlorate, etc., are those toxic-risk is less secure high, there is a problem such as needing attention in use (Non-Patent Documents 1 and 2). It is also reported that could be the use of lithium bromide, to enhance the reactivity under solvent-free conditions at room temperature (Non-Patent Document 3). It is believed that since the liquid at normal temperature and epoxides, amines are used, the method reported in the literature, was achieved by reaction at a high concentration under solvent-free conditions starting material. Thus, a solid at room temperature and can not be applied to epoxides and amines, particularly high melting point.

On the other hand, as described in Patent Document 1, formula 1 compound is produced by ring-opening addition reaction of the amine to the epoxide. In this production process, as the epoxide (2R, 3S) -2 – (2,4 – difluorophenyl) -3 – methyl -2 – [(1H-1, 2,4 – triazol-1 – yl) methyl] oxirane and ( used that methylene piperidine (hereinafter, abbreviated as “4-MP” also) some – is used will hereinafter be abbreviated as “epoxy triazole” also) some, 4 as the amine. In this manufacturing process, it has the disadvantage for heating under reflux for a long time by using the 4-MP solution in large excess in the ring-opening addition reaction, and it is necessary to by-products are produced much in the reaction step to remove them. Furthermore, 4 – methylene-piperidine is prepared by the method described in Patent Document 2, but the purity is low because it is obtained in an aqueous solution, and also affects the reactivity when the distillation isolation there is a problem of impurities by heat generated.

WO 94/26734 pamphlet WO 97/11939 pamphlet

Synthesis, 2004, No.10, pp 1563-1565 J. Org. Chem., 2007, vol. 72, pp 3713-3722 Eur. J. Org. Chem., 2004, No.17, pp 3597-3600

The purpose of the present invention, (2R, 3S) -2 – to oxirane (2,4 – difluorophenyl) -3 – methyl-2 – [methyl-(yl 1H-1, 2,4 – – -1 triazole)] that without using methylene piperidine may yield a compound of Formula 1 under mild conditions to provide a manufacturing method with a reduced formation of by-product – 4 large excess of ring-opening addition reaction of methylene piperidine – 4 some.

As a result of intensive investigations, 4 the present inventors found that – if the acid addition salt of methylene-piperidine, 4 – impurities incorporated in the acquisition phase of the methylene piperidine has been removed, will be isolated as a solid high purity It can, therefore, four of the starting raw material in the ring-opening addition reaction of the amine to epoxy triazole – and that is able to increase the purity of methylene piperidine, the reaction solvent, the ring-opening addition reaction of amines to the epoxy triazole medium, is performed in the presence of hydroxides of alkali metals or alkaline earth metals in particular, 4 – there is no need to use excess methylene piperidine, high yield, by-products and a compound of Formula 1 under mild conditions to discover that it can be produced by reducing things, and have completed the present invention.

I will explain in detail the methods of the present invention are described below.
As indicated by the following reaction formula, the present invention, (2R, 3S) -2 – (2,4 – difluorophenyl) -3 – methyl -2 – [(1H-1, 2,4 – triazol – hydrate thereof or a hydroxide of an alkali metal or alkaline earth metal is selected from the group the reaction solvent, consisting of strontium lithium, sodium, and calcium, and a methylene piperidine acid addition salt and 4 – yl) methyl] oxirane including the presence of a, is reacted relates to a manufacturing method of the formula (1) compound.

Figure JPOXMLDOC01-appb-C000002

(Wherein HX represents an acid addition salt of the acid)

Starting material of the process of the present invention
It can be also performed by using a starting compound of any amount ranging ton level from the g level, the method of the present invention may be determined the amount of solvent depending on the amount of the starting compound used.

(2R, 3S) -2 – (2,4 – difluorophenyl) -3 – methyl -2 – [(1H-1, 2,4 – -1 triazole – yl) methyl] oxirane, JP 2-191262 issue It can be obtained by methods described in the Gazette.
4 – is represented by the following formula methylenepiperidine acid addition salts:

Figure JPOXMLDOC01-appb-C000003

Wherein an acid of the acid addition salts with HX, 4 – The acid forming the methylene piperidine acid addition salts may, for example, hydrochloric, hydrobromic, if an acid that forms a salt with an amine is basically inorganic acid acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, etc.; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p – organic acids such as toluenesulfonic acid and the like, but is not limited thereto. Hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, trifluoroacetic acid and the like, more preferably, preferred examples of the acid is a hydroiodic acid or hydrobromic acid.

4 – methylene-piperidine acid addition salt, 4 – can be obtained by reacting a conventional manner with an acid corresponding to the acid addition salt with methylene piperidine.

Here, the 4 – methylenepiperidine may be preferable in terms of production on an industrial scale, prepared by the method described in WO 97/11939 pamphlet. 4 is manufactured here – methylene-piperidine, and also are obtained in the form of an aqueous solution, impurities produced by heat during the distillation isolation is included, according to the manufacturing method described below, 4 – methylene-piperidine the impurities are removed, acid addition salts can be isolated as a solid high purity.

That is, 4 – preferred method of methylenepiperidine acid addition salts, the following steps:  
(1) 4 – reacting with an acid corresponding to the acid addition salt, a solution of methylene-piperidine, and (2) the solvent is evaporated as necessary, washed suspension crystallization or a product obtained , it is a method comprising the step of purifying.

Here, 4 (1) Step – A solution of methylene piperidine solution in a mixed solvent of alcohol or water and aqueous alcohol solution or (such as methanol), and the like. 0.9-1.0 equivalents is preferably used amount of the methylene piperidine – 4 of the acid corresponding to the acid addition salt. Reaction conditions (1) is carried out at room temperature from 0 ℃, the reaction time is several hours 15 minutes.
After the step (1), if necessary, by conventional methods, for example, under reduced pressure, the temperature is carried out by heating from room temperature solvent was evaporated. In the case of decreasing the water content of the reaction system, for example, by azeotropic toluene or use of the desiccant.
How to purify washed suspension or crystallization in step (2) The method of cleaning is suspended in a solvent crystals or recrystallized after being dissolved in a solvent, obtained by filtration, or distilling off the solvent I may be mentioned.

The acid addition salts, conditions of the production method is different, for example, after the reaction of step (1), the solvent was evaporated, the case of hydrochloride and hydrobromide and acetone crystals was then obtained After washing the suspension and filtered. For p-toluenesulfonate, After the reaction of step (1), the solvent was evaporated, and dissolved in ethyl acetate (10:1) / isopropanol mixture and the residue is recrystallized. For nitrate hydroiodide, and trifluoroacetic acid salt, after the reaction of step (1) to dryness by distilling off the solvent, washed and suspended by addition of diisopropyl ether to the residue.

Reaction conditions of the process of the present invention
4 – triazole for the epoxy, the amount of methylene piperidine acid addition salt is 1 to 5 equivalents, preferably 1 to 1.5 equivalents.

As the hydroxide of alkali metal or alkaline earth metal in the reaction of the present invention, a hydrate thereof or strontium hydroxide lithium hydroxide, sodium hydroxide, calcium hydroxide and the like. More preferably, lithium hydroxide, a hydrate thereof or calcium hydroxide, more preferably a hydrate thereof or a lithium hydroxide.

The amount of the hydroxide of alkaline earth metals varies depending on the basicity and the type of compound used or the alkali metals, 4 – for methylenepiperidine acid addition salt is 1 to 5 equivalents usually preferably is 1 to 1.5 equivalents.


Production Example 1
Methanol / water mixture methylene piperidine (4-MP) – 4 obtained by the method described in the manufacture WO 97/11939 pamphlet methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 was cooled by stirring in an ice bath under a solution 0.8M 500mL (0.4mol). Thereafter, the solution is added in several portions (0.36mol) 48% hydrobromic acid 61.3g, followed by stirring for 1 hour in an ice bath. Thereafter, to precipitate white crystals by evaporating the solvent by heating under reduced pressure. Subsequently, we conducted two times operation for azeotropic water by distilling off the solvent by heating under reduced pressure and toluene was added to 50mL, and added acetone 192mL, was 2 hours under stirring ice bath. Thereafter, The crystals are filtered, washed crystals with 60mL (cooled in an ice bath) of acetone, 4-MP · HBr58g as colorless crystals (yield: 90%) After air-drying at room temperature, for 12 hours and dried under reduced pressure at 40 ℃ I got.
1 H-NMR (500MHz, CDCl 3)
δ: 2.62 (4H, t, J = 6.09 Hz), 3.26 (4H, t, J = 6.09 Hz), 4.90 (2H, s), 9.18 (1H, br).
Melting point (DSC): 147 ~ 147.9 ℃

Production Example 2
Water removal operation (4-MP) methylene piperidine – 4 obtained by the method described in the manufacture WO 97/11939 pamphlet methylene piperidine p-toluenesulfonic acid salt of (4-MP · PTSA) – 4 isopropanol (9.7g, 0.1mol) of (IPA) in (50mL) solution, 4-MP, which is subjected to, the resulting p-toluenesulfonic acid monohydrate (PTSA · H 2 O) (18.1g, 0.095mol) / was added (80mL) IPA, (weak exothermic) after which the mixture was stirred for 30 minutes at room temperature, evaporated under reduced pressure IPA, and was heated and dissolved in (250mL) with ethyl acetate / IPA mixture = 10:1 residue. After cooling to room temperature and allowed to stand for 20 hours at 0 ~ 5 ℃, filtered washing the precipitated crystals were obtained (91.2% yield) 4-MP · PTSA 23.34g of white crystals to dry.
1 H-NMR (400MHz, DMSO-d 6)
δ: 2.29 (3H, s), 2.35 (4H, t, J = 6.4 Hz), 3.08 (4H, t, J = 6.4 Hz), 4.85 (2H, s), 7.13 (2H, d, J = 8.2 Hz ), 7.49 (2H, d, J = 8.2 Hz), 8.58 (2H, brs).

Production Example 3
4 obtained by the method described in the manufacture WO 97/11939 pamphlet methylene piperidine hydrochloride (4-MP · HCl) – – 4 subjected to moisture removal operation methylene piperidine (4-MP), obtained was cooled by stirring in an ice bath under (4.12mol) 4-MP 400g that is. Thereafter, the solution was added concentrated hydrochloric acid and 350mL (4.08mmol), and the mixture was stirred in an ice bath. After concentration under reduced pressure was performed 3 times operation for azeotropic water and concentrated under reduced pressure and toluene was added to 300mL. The washed suspension under ice-cooling and addition of acetone 300mL. The filtered crystals were washed with acetone crystals, 4 and dried under reduced pressure at room temperature – was obtained (46% yield) methylene-piperidine hydrochloride (4-MP · HCl) 336.8g.
1 H-NMR (500MHz, CDCl 3)
δ: 2.58 (4H, t, J = 6.1Hz), 3.22 (4H, t, J = 6.1Hz), 4.89 (2H, s), 9.70 (1H, br s).

Preparation Example 4
Methanol / water mixture methylene piperidine (4-MP) – 4 obtained by the method described in the manufacture WO 97/11939 pamphlet methylene piperidine hydriodic acid salt of (4-MP · HI) – 4 was cooled by stirring in an ice bath under a solution 0.66M 20mL (13.19mmol). Thereafter, the solution was added 57% hydroiodic acid and 2.66g (11.84mmol), and the mixture was stirred for 15 minutes in an ice bath. After concentrated under reduced pressure, to precipitate a white solid by performing twice the operation for azeotropic water and concentrated under reduced pressure and toluene was added to 1.6mL. The washed suspension for 1 hour at room temperature by addition of diisopropyl ether 6mL. Thereafter, The crystals are filtered, washed and crystallized with diisopropyl ether, 4 and dried under reduced pressure at room temperature – was obtained (90% yield) methylene piperidine hydroiodide (4-MP · HI) 2.66g.
1 H-NMR (500MHz, CDCl 3)
δ: 2.66 (4H, t, J = 6.1Hz), 3.31-3.33 (4H, m), 4.91 (2H, s), 8.34 (1H, br s).

Preparation Example 5
The reaction was carried out similarly to the above method by using trifluoroacetic acid (TFA) 1.35g and (11.87mmol) in place of hydriodic acid production 57% methylene piperidine trifluoroacetate salt of (4-MP · TFA), – 4 I got a (92% yield) methylene piperidine trifluoroacetate (4-MP · TFA) 2.55g – 4.
1 H-NMR (500MHz, CDCl 3)
δ: 2.50 (4H, t, J = 6.1Hz), 3.16 (4H, t, J = 6.1Hz), 4.89 (2H, s), 9.52 (1H, br s).

Preparation Example 6
The reaction was carried out in the same manner as the above-described method using 69% nitric acid 1.08g the (11.87mmol) instead of hydroiodic acid production 57% methylene piperidine nitrate (4-MP · HNO 3), 4 – – 4 methylenepiperidine nitrate I got a (89% yield) (4-MP · HNO 3) 1.87g.
1 H-NMR (500MHz, CDCl 3)
δ: 2.53 (4H, t, J = 6.1Hz), 3.28 (4H, t, J = 6.1Hz), 4.89 (2H, s), 8.85 (1H, br s).

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)

Example 2
Epoxy triazole 0.50g (1.99mmol), 4 – in addition to acetonitrile 2mL lithium hydroxide 0.07g methylene piperidine hydrobromide (4-MP · HBr) 0.53g and (2.98mmol) and (2.96mmol), oil bath ( I was heated under reflux for 14 hours at an external temperature of 100 ℃). After the solvent was evaporated under reduced pressure of the reaction solution obtained, the solution was separated by the addition of ethyl acetate and water to the residue. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (1:1) hexane / ethyl acetate solvent, to give (86% yield) KP-103 0.59g.

Example 3
The reaction was carried out in the same manner as in Example 2 using the calcium hydroxide 0.22g (2.97mmol) instead of lithium hydroxide, to give (82% yield) KP-103 0.57g.

Example 4
Was performed for 19 hours and the reaction in the same manner as in Example 2 using strontium hydroxide 0.36g a (2.98mmol) in place of lithium hydroxide, to give (68% yield) KP-103 0.47g.

Example 5
Was added 2mL of acetonitrile lithium hydroxide monohydrate 0.13g methylene piperidine hydrobromide (4-MP · HBr) 0.53g and (2.98mmol) and (2.96mmol) – epoxy-triazole 0.50g (1.99mmol), 4 , I was heated under reflux for 14 hours at (external temperature of 100 ℃) oil bath. Was determined to (relative area percentage of KP-103) reaction rate by HPLC measurements by sampling the reaction mixture, it was confirmed the formation of KP-103 at 81% response rate.

Example 6
The reaction was carried out in the same manner as in Example 2 using cyclopentyl methyl ether (CPME) 2mL instead of acetonitrile, to give (91% yield) KP-103 0.63g.

Example 7
1,2 instead of acetonitrile – The reaction was carried out in the same manner as in Example 2 using dimethoxyethane (DME) 2mL, was obtained (79% yield) KP-103 0.55g.

Example 8
1 in place of acetonitrile – The reaction was carried out in the same manner as in Example 2 using butanol 2mL, was obtained (72% yield) KP-103 0.59g.

Example 9
The reaction was carried out in the same manner as in Example 2 using isopropanol 2mL instead of acetonitrile, to give (86% yield) KP-103 0.50g.

Example 10
Methyl – 2 – 4 instead of acetonitrile reaction was carried out in the same manner as in Example 2 using the pentanone (MIBK) 2mL, to give (88% yield) KP-103 0.61g.

Example 11
Example Using methylene piperidine hydrochloride (4-MP · HCl) 0.40g and (2.99mmol) – 4 obtained in Production Example 3 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 The reaction was carried out in the same manner as 2, was obtained (67% yield) KP-103 0.47g.

Example 12
Using methylene piperidine hydroiodide (4-MP · HI) 0.67g and (2.99mmol) – 4 obtained in Production Example 4 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 The reaction was carried out in the same manner as in Example 2 upgrade does not give (90% yield) KP-103 0.62g.

Example 13
Using methylene piperidine trifluoroacetate (4-MP · TFA) 0.63g and (2.98mmol) – 4 obtained in Production Example 5 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 The reaction was carried out in the same manner as in Example 2, was obtained (78% yield) KP-103 0.54g.

Example 14
Example Using methylenepiperidine nitrate (4-MP · HNO 3) 0.48g and (3.00mmol) – 4 obtained in Production Example 6 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 The reaction was carried out in the same manner as 2, was obtained (71% yield) KP-103 0.49g.

Example 15
Methylenepiperidine hydroiodic acid – 4 obtained in Production Example 4 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – Sodium hydroxide 0.12g (2.98mmol), 4 instead of lithium hydroxide was performed 18 hours and the reaction in the same manner as in Example 2 using salt (4-MP · HI) 0.67g and (2.99mmol), to give (73% yield) KP-103 0.51g.

Conventional methods for producing formula 1 compound of the starting material 4 – impurity contamination at the acquisition stage of methylene piperidine, and by-products to be produced during the manufacture of the formula 1 compound was a problem. In the method of the present invention, as a starting material of the production method of the formula 1 compound, 4 – by making the acid addition salt of methylene-piperidine, 4 – impurities incorporated in the acquisition phase of the methylene piperidine has been removed, high purity it is possible to use a solid. In the method of the present invention, since the ring-opening addition of the amine to epoxy triazole is promoted, 4 – there is no need to use excess methylene piperidine, high yield, and by-products of the compound of Formula 1 under mild conditions It can be produced by reducing compound. Therefore, by the method of the present invention to produce an industrial scale formula 1 compound became possible.

Patent Citations
Cited Patent Filing date Publication date Applicant Title
WO1994026734A1 May 2, 1994 Nov 24, 1994 Tadashi Arika Azolylamine derivative
WO1997011939A1 Sep 26, 1996 Apr 3, 1997 Kaken Pharma Co Ltd Process for the preparation of 4-methylenepiperidines
JPH02191262A Title not available
Non-Patent Citations
Reference
1 EUR. J. ORG. CHEM. 2004, pages 3597 – 3600
2 J. ORG. CHEM. vol. 72, 2007, pages 3713 – 3722
3 * MIMURA, MITSUO ET AL.: ‘Synthesis and evaluation of (piperidinomethylene)bis (phosphonic acid) derivatives as anti- osteoporosis agents‘ CHEMICAL & PHARMACEUTICAL BULLETIN vol. 41, no. 11, 1993, pages 1971 – 1986
4 * OGURA, HIRONOBU ET AL.: ‘Synthesis and antifungal activities of (2R,3R)-2-aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives as topical antifungal agents‘ CHEMICAL & PHARMACEUTICAL BULLETIN vol. 47, no. 10, 1999, pages 1417 – 1425, XP002296880
5 SYNTHESIS 2004, pages 1563 – 1565
PATENTS
10-6-1999
Azolylamine derivative
2-11-1998
Azolylamine derivative
12-18-1997
AZOLYLAMINE DERIVATIVE
4-16-1997
Azolylamine derivative

References

  1. Patel T, Dhillon S (Nov 2013). “Efinaconazole: first global approval”. Drugs 73 (17): 1977–1983. doi:10.1007/s40265-013-0152-x. PMID 24249649.
  2. Tschen EH, Bucko AD, Oizumi N, Kawabata H, Olin JT, Pillai R (Feb 2013). “Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study”. J Drugs Dermatol 12 (2): 186–192. PMID 23377392.
  3. Tatsumi Y, Nagashima M, Shibanushi T, et al. (May 2013). “Mechanism of action of efinaconazole, a novel triazole antifungal agent”. Antimicrob Agents Chemother 57 (5): 2405–2509.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.




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1 Comment

  1. Ralph Anderson says:

    The company sells 4ml and 8ml bottles. The number of drops in a bottle is so low that they are a rip off. Doctors are prescribing small amounts causing consumers to pay a huge amount over the 48 weeks. Intentional misinformation to prescribers is causing a problem.

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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