CLIAMS:1. A process for the preparation compound of Formula II:

Formula II
wherein the ring X is fluorine which is substituted at 4th or 5th position at benzene ring.
which comprises:

a) reaction of 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid to provide 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine; and
b) reaction of 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine with 1,3- or 1,4-difluorobenzene in presence of n-hexyl lithium to provide the compound of Formula II.

2. The process of claim 1, wherein the step a) is carried out in the presence of solvent such as chlorinated solvent.

3. The process of claim 1, wherein the quantity of trifluoroacetic acid is about 0.1 to 1 molar equivalents per equivalent of 4-[(R)-2-Hydroxypropionyl] morpholine.

4. The process of claim 1, wherein the step b) is conducted in presence of solvent such as tetrahydrofuran.

5. A process for the preparation of compound of Formula IIA:

Formula IIA
which comprises:

a) reaction of 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid to provide 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine; and
b) reaction of 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine with 1,4-difluorobenzene in presence of n-hexyl lithium to provide the compound of Formula II.
,TagSPECI:Field of Invention

Aspects of the present invention relates to a process for the preparation of intermediate of azole derivative. In a further aspect, the present invention relates to a process for the preparation of (2R)-2’, 5’-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone or a pharmaceutically acceptable slat thereof, which is a key intermediate of Isavuconazole.

Background of the invention

Isavuconazole, isavuconazonium, Voriconazole, and Ravuconazole are Azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238.

The US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol; and has the structural formula I:

Formula I
The reported process for the intermediate of azole derivative of formula II is disclosed in the Scheme 1:

Further, U.S. Patent No. 7,816,537 discloses a process for the preparation of intermediate of isavuconazole, (2S)-2’, 5’-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone, which involves reaction of 1,4-difluorobenzene with (2S)-1-Morpholin-4-yl-2-(tetrahydro-pyran-2-yloxy)-propan-1-one in presence of base such as lithium diisopropylamine, and solvent such as THF/heptane. The process is shown in the following scheme-2:

The reported process suffers one or the other problems like yield and purity due to the reagents and reaction condition. Hence, there is a need for a simple process for making large scale quantities of intermediate of azole derivative.

Summary of the Invention

The present invention provides a process for the preparation azole intermediate and its conversion to azole derivative such as Isavuconazole, Ravuconazole and the like.

In an aspect, the present invention provides a process for the preparation of compound of Formula II:

Formula II
wherein the ring X is fluorine which is substituted at 4th or 5th position at benzene ring.
which comprises:

a) reaction of 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid to provide 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine; and
b) reaction of 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine with 1,3- or 1,4-difluorobenzene in presence of n-hexyl lithium to provide the compound of Formula II.

In another aspect, the present invention provides a process for the preparation of compound of Formula IIA:

Formula IIA
which comprises:

a) reaction of 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid to provide 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine; and
b) reaction of 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine with 1,4-difluorobenzene in presence of n-hexyl lithium to provide the compound of Formula II.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The compound of formula II, IIA, intermediates and starting materials of the present invention may be prepared/used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

In an aspect, the present invention provides a process for the preparation of compound of Formula II:

Formula II
wherein the ring X is fluorine which is substituted at 4th or 5th position at benzene ring.
which comprises:

a) reaction of 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid to provide 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine; and
b) reaction of 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine with 1,3- or 1,4-difluorobenzene in presence of n-hexyl lithium to provide the compound of Formula II.

The step a) involves reaction of 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid to provide 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine.

The reaction is carried out at a temperature of about -5 to 40 °C or 0 to 15 °C. The reaction mixture may be stirred for a period of about 15 minutes to 1 hour or more at the same temperature.

The reaction of step a) may be carried out in presence of solvent which includes but are not limited to chlorinated solvents such as dichloromethane, chloroform, chlorobenzene and the like.

The quantity of trifluoroacetic acid may range from 0.1 to 1 molar equivalent per equivalent of 4-[(R)-2-Hydroxypropionyl] morpholine. The addition of trifluoroacetic acid may be performed at 0 to 20 °C for a period of 5 minutes to 30 minutes while controlling the exothermic reaction.

After completion of the reaction, the reaction mixture may be washed with basic solution and subjected for concentration or isolation of solid using suitable known techniques such as recrystallization, stripping off the solvent, anti-solvent technique and the like.

The step b) involves reaction of 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine with 1,3- or 1,4-difluorobenzene in presence of n-hexyl lithium to provide the compound of Formula II.

The reported processes of the prior art require conversion of substituted benzene to its bromoderivatives or use of expensive bases like lithium diisopropylamine to facilitate the condensation and made the process expensive.

The present inventors found that the use of selective base such as n-hexyl lithium provides direct condensation of 1,3- or 1,4-difluorobenzene with 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine and gives higher yield and purity.

The reaction is performed in presence of solvent includes but are not limited to ether such as tetrahydrofuran, diisopropyl ether and the like; hydrocarbon such as hexane, heptane and the like; or in combination thereof.

The reaction is conducted at a temperature of about -20 to about 40 °C or at about -5 to 0 °C. The reaction may be performed for a period of about 30 minutes to 3 hours or more.

After completion of the reaction, the reaction mixture may be quenched with quenching agent such as ammonium chloride solution and then extracted into organic solvent such as ethyl acetate. The obtained organic layer may be concentrated or subjected for isolation of solid using column chromatography or recrystallization techniques or both.

In another aspect, the present invention provides a process for the preparation of compound of Formula IIA:

Formula IIA
which comprises:

a) reaction of 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid to provide 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine; and
b) reaction of 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine with 1,4-difluorobenzene in presence of n-hexyl lithium to provide the compound of Formula II.

The step a) is carried out at a temperature of about 0 to 15 °C in presence of solvent such as dichloromethane.

The quantity of trifluoroacetic acid for step a) may range from 0.1 to 1 molar equivalent per equivalent of 4-[(R)-2-Hydroxypropionyl] morpholine. The addition of trifluoroacetic acid may be performed at 0 to 20 °C for a period of 5 minutes to 30 minutes while controlling the exothermic reaction.

After completion of the reaction, the reaction mixture may be washed with basic solution and subjected for concentration or used directly for further reaction.

The step b) is performed in presence of solvent includes but are not limited to ether such as tetrahydrofuran, diisopropyl ether and the like; hydrocarbon such as hexane, heptane and the like; or in combination thereof.

After completion of the reaction, the reaction mixture may be quenched with quenching agent such as ammonium chloride solution and then extracted into organic solvent such as ethyl acetate. The obtained organic layer may be concentrated or subjected for isolation of solid using column chromatography or recrystallization techniques or both.

The resultant compound of formula II and IIA is useful for the preparation of azole derivatives. The compound of formula IIA is a key intermediate and is useful for the preparation of isavuconazole and isavuconazonium.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example-1:

Process for enantiomerically pure intermediates (2R)-2’, 5’-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone

A solution of Methyl (R)-Lactate (100 g, 0.9606 mol) and Morpholine (250 g, 2.881 mol) was stirred for 40 hours at 85 °C. The solution of morpholine was evaporated under reduced pressure to afford crude 4-[(R)-2-Hydroxypropionyl] morpholine (162.0 gm crude) as pale yellow thick oil.

This crude Product is directly used for next step without purification.

1H NMR, dppm (CDCl3-d): 1.31 – 1.32 (3H, d, J= 6.4 Hz), 3.41 ((2H, t, J= 4.7 Hz), 3.54-3.82 (7H, m), 4.41- 4.53 (1H, q, J= 6.6 Hz).

Mass Spectrometry: The protonated molecular ion at m/z 160.0 (M+1) confirms the mass.

Example -2:
Preparation of 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine

The mixture of 4-[(R)-2-Hydroxypropionyl] morpholine (160 g, 1.005 mol) in DCM was cooled to 15 °C. Trifluoroactic acid (34.3 gm, 0.3015 mol) was added into it. The reaction mixture was cooled to 10 °C and 1,4-dihydropyran (110 g, 1.3066 mol) was added in to it at 10-15 °C. The reaction mixture was stirred for 1 hour at room temperature and then washed with aqueous sodium bicarbonate. The reaction solution was dried over anhydrous sodium sulfate and distilled out the solvent under reduced pressure to afford crude 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine (200.0 g) as a pale yellow oil.

1H NMR, dppm (CDCl3): 1.38, 1.42 (3H, d, each J= 6.8 Hz), 1.50-1.84 (6H, m, broad), 3.44- 3.86 (10H, m), 4.50-4 .66 (2H, m).

Mass Spectrometry: The protonated molecular ion at m/z 244.1 (M+) confirms the mass.

Example-3:

Preparation of (2R)-2’, 5’-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone

1,4-Difluoro benzene (10.5gm, 0.092 mol) was dissolved in 20 ml anhdyrous tetrahydrofuran. The mixture was cooled to –5 to 0 °C. N-hexyllithium (33% in n-hexane) (36.8 ml, 0.092 mol) was added drop wise over period of 10 minutes to the reaction mixture and stirred for 15 minutes at 0°C. 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine (15.0 gm, 0.0616 mol) was dissolved in tetrahydrofuran (40 ml) and then added dropwise in to the reaction mixture over a 10 minutes at –5 to 0 °C. The mixture was stirred for 120 minutes at 0 °C. After the completion of the reaction, the mixture was quenched with sat. NH4Cl solution. The reaction mixture was extracted into ethyl acetate and then th organic phase was washed with water followed by brine solution. The resultant organic phase was dried over anhydrous Na2SO4. It was filtered and the solvent was distilled out under vacuum. The crude product was purified by column using silicagel to afford 7.3 gm light yellowish oily product.

Proton NMR in CDCl3 is identical with published Patent US 6,300,353.
Mass Spectrometry: The protonated molecular ion at m/z 271.2 (M+) confirms the mass.