WO2015150947A1 - A process for the preparation of isavuconazole and its intermediates - Google Patents

A process for the preparation of isavuconazole and its intermediates Download PDF

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Publication number
WO2015150947A1
WO2015150947A1 PCT/IB2015/051941 IB2015051941W WO2015150947A1 WO 2015150947 A1 WO2015150947 A1 WO 2015150947A1 IB 2015051941 W IB2015051941 W IB 2015051941W WO 2015150947 A1 WO2015150947 A1 WO 2015150947A1
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difluorophenyl
solvent
yloxy
pyran
tetrahydro
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PCT/IB2015/051941
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French (fr)
Inventor
Rupesh Chhaganbhai KHUNT
Rambhupal REDDY
Mohammad Rafeeq
Arvind Yekanathsa Merwade
Keshav Deo
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Wockhardt Limited
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Priority claimed from IN1193MU2014 external-priority patent/IN2014MU01193A/en
Publication of WO2015150947A1 publication Critical patent/WO2015150947A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to a process for the preparation of Isavuconazole or its pharmaceutical acceptable salt thereof.
  • aspects of the present invention relates to a process for the preparation of intermediate of propan-l-one intermediate.
  • the present invention relates to a process for the preparation of triazole intermediate.
  • the present invention relates to a process for the preparation of oxirane intermediate.
  • 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 propan-1- one intermediate is converted to epoxide intermediate in dimethyl sulfoxide solvent and subsequently to (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)- 1 -( 1H- l,2,4-triazol-l-yl)butan-2-ol (referred herein after "triazole intermediate") in presence of strong base sodium hydride.
  • the triazole intermediate is further converted to mesylate intermediate which is then converted to l-(((2R,3S)-2-(2,5-difluorophenyl)-3- methyloxiran-2-yl)methyl)-lH-l,2,4-triazole (referred herein after "oxirane intermediate") using strong base sodium methoxide in methanol.
  • oxirane intermediate l-(((2R,3S)-2-(2,5-difluorophenyl)-3- methyloxiran-2-yl)methyl)-lH-l,2,4-triazole
  • U.S. Patent No. 7,816,537 discloses other process a process for the preparation of intermediate of Isavuconazole.
  • the present invention provides a process for the preparation of Isavuconazole pharmaceutical acceptable salt thereof, compound of formula I
  • the process includes the steps of,
  • the present invention provides conversion of Isavuconazole to Isavuconazonium and its sulfate or iodide hydrochloride salt.
  • the present invention provides a process for the preparation of Isavuconazole intermediates, e.g. propan-l-one, triazole, oxirane intermediates, which is a key intermediates of Isavuconazole.
  • Isavuconazole intermediates e.g. propan-l-one, triazole, oxirane intermediates, which is a key intermediates of Isavuconazole.
  • the present invention provides a process for the preparation of compound of Formula II
  • the present invention provides a process for the preparation of compound of Formula IIA
  • the process includes the step of ;
  • the present invention provides a process for the preparation of (R)-2-(2,5- difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl) butan-2-ol, compound of Formula III,
  • the process includes the steps of; a) adding 1,2,4-triazole with trimethylsulfoxonium iodide in a aprotic solvent, b) contacting the solution of (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2- yloxy)propan-l-one in aprotic solvent with the reaction mixture of step a), c) isolating (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)- 1-( 1H- l,2,4-triazol-l-yl)butan-2-ol from the reaction mixture thereof.
  • the present invention provides conversion of (R)-2-(2,5-difluorophenyl)-3- (tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol to Isavuconazole, Isavuconazonium and its sulfate or iodide hydrochloride salt.
  • the present invention provides a process for the preparation of l-(((2R,3S)-2-(2,5- difluorophenyl)-3-methyloxiran-2-yl)methyl)-lH- 1,2,4-triazole, compound of Formula
  • the process includes the steps of,
  • step b c) contacting aqueous solution of base with the reaction mixture of step b), d) isolating l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1,2,4-triazole from the reaction mixture thereof.
  • the present invention provides conversion of l-(((2R,3S)-2-(2,5- difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1 ,2,4-triazole to Isavuconazole, Isavuconazonium and its sulfate or iodide hydrochloride salt.
  • the compound of formula II, IIA, III and IV intermediates and starting materials of the present invention may be prepared and /or 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.
  • the present invention provides a process for the preparation of Isavuconazole or its pharmaceutical acceptable salt thereof compound of formula I
  • the process includes the steps of;
  • the present invention provides a process for the preparation of compound of Formula II
  • ring X is fluorine, which is substituted at 4 or 5 position at benzene ring, the process includes the step of;
  • the step a) involves condensing 4-[(R)-2-hydroxypropionyl] morpholine with 1,4- dihydropyran in presence of trifluoroacetic acid to obtain (R)-l-morpholino-2- (tetrahydro-2H-pyran-2-yloxy)propan- 1 -one.
  • the reaction is carried out at temperature in between range of -5°C to 40 °C.
  • the reaction mixture may be stirred for a period of about 15 minutes to 1 hour or more at the same temperature for completion.
  • step a) may be carried out in presence of halogenated solvent, wherein halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof.
  • halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof.
  • the quantity of trifluoro acetic 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 temperature in between range of 0°C to 20 °C for a period of 5 minutes to 30 minutes, while controlling the exothermicity of the reaction.
  • 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 in a solvent to obtain the compound of Formula II, wherein solvent is selected from the group comprising one or more of ether solvent and hydrocarbon solvent and mixture thereof, ether solvent is selected from the group comprising one or more of tetrahydrofuran and diisopropyl ether; hydrocarbon is selected from the group comprising one or more of hexane and heptane.
  • 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 conducted at temperature in between range of -20°C to 40 °C or at -5°C to 0 °C.
  • the reaction may be performed for a period of about 30 minutes to 3 hours or more.
  • the reaction mixture may be quenched with 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 present invention provides a process for the preparation of compound of Formula IIA
  • the process includes the step of;
  • the step a) is carried out at a temperature of about 0 to 15 °C in presence of halogenated, wherein halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof.
  • halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof.
  • 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 exothermicity of the reaction.
  • step b) of the present invention involves the reacting (R)-l-morpholino-2- (tetrahydro-2H-pyran-2-yloxy)propan- 1 -one with 1,4-difluorobenzene in presence of n- hexyl lithium in a solvent, wherein solvent is selected from the group comprising one or more of tetrahydrofuran, diisopropyl ether, hexane, heptane and mixture thereof.
  • reaction mixture may be quenched with ammonium chloride solution and then extracted into organic solvent such as ethyl acetate.
  • 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 present invention provides conversion of compound of formula II and compound of formula IIA to Isavuconazole, Isavuconazonium and its sulfate or iodide hydrochloride salt.
  • the present invention provides a process for the preparation of (R)-2-(2,5- difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl) butan-2-ol, compound of Formula II,
  • the process includes the steps of;
  • step a) a) adding 1,2,4-triazole with trimethylsulfoxonium iodide in a aprotic solvent, b) contacting the solution of 2,4-difluoro propiophenone in aprotic solvent with the reaction mixture of step a),
  • the reaction is performed in aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2- pyrrolidone, tetrahydrofuran and mixture thereof.
  • the base may be selected from the group comprising one or more of organic base and inorganic base, wherein organic base is selected from the group comprising one or more of ammonia, dimethylamine, diethylamine or triethylamine, potassium t- butaoxide; inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
  • 2,4-difluoro propiophenone solution in aprotic solvent at temperature between in range of 60 °C to 85 °C is added.
  • the aprotic solvent comprises one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane, tetrahydrofuran and N- methyl-2-pyrrolidone, and mixture thereof.
  • the reaction mixture is quenched with water at temperature between in range of 10°C to 20°C and finally extracted with ethyl acetate.
  • the step (a) to (c) may be carried out using a one -pot procedure.
  • reaction mixture After completion of the reaction, the reaction mixture may be subjected for concentration or isolation of solid using suitable known techniques such as recrystallization, stripping off the solvent, anti-solvent technique and the like. After completion of the reaction, the reaction mixture may be quenched with water. The obtained organic layer may be concentrated or subjected for isolation of solid using column chromatography or recrystallization techniques or both.
  • the present invention provides a process for the preparation of 1- (((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1 ,2,4-triazole, compound of Formula II,
  • the process includes the steps of;
  • the (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-diol is dissolved in a organic solvent with base at temperature between in range of 20 °C to 30 °C, followed by drop wise addition of mesyl chloride at temperature between in range of 10 °C to 15 °C.
  • the reaction is stirred for 1 to 2 hour at temperature between in range of 15 °C to 30 °C, wherein organic solvent is selected from the group comprising one or more of chloroform, dichloromethane, dichloroethane, chlorobenzene, carbon tetrachloride and water mixture thereof.
  • the step (c) of the present invention involves the addition of 10% to 20 % aqueous solution of base in the reaction mixture, followed by stirring the biphasic reaction for period of 2 to 4 hour at temperature between in range of 15 °C to 30 °C.
  • the base may be selected from the group comprising one or more of organic base and inorganic base, wherein organic base is selected from the group comprising one or more of ammonia, dimethylamine, diethylamine or triethylamine, potassium t-butoxide; inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
  • Isolation involves the removal of organic solvent by means of distillation under reduced pressure to get the l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran -2-yl)methyl)-lH- 1,2,4-triazole as light yellowish oil.
  • the step (a) to (c) may be carried out using a one -pot procedure.
  • reaction mixture may be subjected for concentration or isolation of solid using suitable known techniques such as recrystallization, stripping off the solvent, anti-solvent technique and the like.
  • reaction mixture may be quenched quenching agent such as water.
  • quenching agent such as water.
  • the obtained organic layer may be concentrated or subjected for isolation of solid using column chromatography or recrystallization techniques or both.
  • triazole intermediate obtained l-(((2R,3S)-2- (2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-lH-l,2,4-triazole according to process of the invention converted to converted to Isavuconazole or its salt to Isavuconazonium iodide hydrochloride and subsequently Isavuconazonium sulfate.
  • Example-4 The preparation of (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2- yloxy)- 1-( 1H- 1,2,4-triazol- l-yl)butan-2-ol Charged (400 ml) tetrahydrofuran, (500 ml) dimethylformamide, 33.1 gm 1,2,4-triazole and 105.6 gm trimethyl sulfoxonium iodide in a flask. The reaction mixture was cooled at temperature between in range of 8 °C - 10 °C and potassium i-butoxide (102.9 gm) was added lot wise.
  • Example-5 The preparation of (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l- yl)butane-2,3-diol
  • Example-6 Preparation of l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2- yl)methyl)- 1H- 1 ,2,4-triazole Charged dichloromethane (400 ml) and (2R,3R)-2-(2,5-difluoro phenyl)-l-(lH-l,2,4- triazol-l-yl)butane-2,3-diol (40 gm) in a round bottom flask.
  • triethylarnine (30 gm) was added drop wise at room temperature.
  • reaction mixture was cooled at temperature between in range of 10°C to 15°C and mesyl chloride (21.2 gm) was added drop wise at temperature between in range of 10°C to 15°C to the said reaction mixture.
  • mesyl chloride reaction was stirred for 1-2 hours at temperature between in range of 15°C to 25°C.
  • 10 % aqueous Potassium carbonate solution 400 ml was added in to the reaction mixture and furhter stirred for 1-2 hours at temperature between in range of 15°C to 25°C.
  • dichloromethane layer was separated and dichloromethane was distillation out to get the title compound as light yellowish oily product.

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Abstract

The present invention relates to a process for the preparation of Isavuconazole or its pharmaceutical acceptable salt thereof. In particular aspects of the present invention relates to a process for the preparation of intermediate of azole intermediate. In a further aspect, the present invention relates to a process for the preparation of triazole intermediate. In a further aspect, the present invention relates to a process for the preparation of oxirane intermediate.

Description

A PROCESS FOR THE PREPARATION OF ISAVUCONAZOLE AND ITS
INTERMEDIATES
Field of Invention
The present invention relates to a process for the preparation of Isavuconazole or its pharmaceutical acceptable salt thereof. In particular aspects of the present invention relates to a process for the preparation of intermediate of propan-l-one intermediate. In a further aspect, the present invention relates to a process for the preparation of triazole intermediate. In a further aspect, the present invention relates to a process for the preparation of oxirane intermediate.
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 (referred herein after '353 US Pat.) discloses Isavuconazole and its process. It has chemical name 4-[2-[(lR,2R)-2-(2,5-difluorophenyl)-2-hydroxy-l- methyl-3-(l,2,4-triazol-l-yl)propyl]thiazol-4-yl]benzonitrile and has the structural formula I
Figure imgf000002_0001
Formula I The '353 US Patent reports the process for the Isavuconazole with its key intermediates as depicted in the Scheme 1:
Figure imgf000003_0001
Formula-Ill
Formula-IIA
Figure imgf000003_0002
Formula-IV
Scheme-1
The '353 US Patent disclosed process for the preparation of Isavuconazole, which involves formation of (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2- yloxy)propan-l-one (referred herein after "propan- 1 -one intermediate"). The propan-1- one intermediate is converted to epoxide intermediate in dimethyl sulfoxide solvent and subsequently to (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)- 1 -( 1H- l,2,4-triazol-l-yl)butan-2-ol (referred herein after "triazole intermediate") in presence of strong base sodium hydride. The triazole intermediate is further converted to mesylate intermediate which is then converted to l-(((2R,3S)-2-(2,5-difluorophenyl)-3- methyloxiran-2-yl)methyl)-lH-l,2,4-triazole (referred herein after "oxirane intermediate") using strong base sodium methoxide in methanol. The said reported processes have many drawbacks such as it involves tedious workup, use of hazardou and difficult to handle bases, distillation of high boiling solvent and involvement of additional step of mesylate intermediate formation.
U.S. Patent No. 7,816,537 discloses other process a process for the preparation of intermediate of Isavuconazole.
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.
Su miliary of the Invention
The present invention provides a process for the preparation of Isavuconazole pharmaceutical acceptable salt thereof, compound of formula I
Figure imgf000004_0001
Formula I
the process includes the steps of,
a) condensing 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoro acetic acid in a halogenated solvent to obtain (R)-l-morpholino- 2-(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one,
b) reacting (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,4- difluorobenzene in presence of n-hexyl lithium in a solvent to obtain the compound of (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one, c) contacting (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,2,4-triazole and trimethylsulfoxonium iodide in a aprotic solvent to obtain (R)- 2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l- yl)butan-2-ol,
d) converting (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH- 1,2,4- triazol-l-yl)butan-2-ol in to (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l- yl)butane-2,3-diol,
e) reacting (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-diol with mesyl chloride in presence of base in a halogenated solvent to obtain l-(((2R,3S)-2- (2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1 ,2,4-triazole,
f) converting 1 -(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1,2,4-triazole to Isavuconazole or its pharmaceutical acceptable salt thereof.
In an aspect, the present invention provides conversion of Isavuconazole to Isavuconazonium and its sulfate or iodide hydrochloride salt.
In another aspect, the present invention provides a process for the preparation of Isavuconazole intermediates, e.g. propan-l-one, triazole, oxirane intermediates, which is a key intermediates of Isavuconazole.
In another aspect, the present invention provides a process for the preparation of compound of Formula II
Figure imgf000005_0001
Formula II
wherein the ring X is fluorine, which is substituted at 4 or 5 position at benzene ring, the process includes the step of
a) condensing of 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoro acetic acid in a halogenated solvent to obtain (R)-l-morpholino- 2-(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one, b) reacting (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,3- or 1 ,4-difluorobenzene in presence of n-hexyl lithium in a solvent to obtain the compound of Formula II.
In another aspect, the present invention provides a process for the preparation of compound of Formula IIA
Figure imgf000006_0001
Formula IIA
the process includes the step of ;
a) reacting 4-[(R)-2-hydroxypropionyl] morpholine with 1 ,4-dihydropyran in presence of trifluoroacetic acid in a halogenated solvent to obtain 4-[(2R)-2-(3, 4,5,6- tertahydro-2H-pyran-2-yloxy)propionyl] morpholine,
b) reacting 4-[(2R)-2-(3,4,5,6-tertahydro-2H-pyran-2-yloxy)propionyl] morpholine with 1,4-difluorobenzene in presence of n-hexyl lithium in a solvent to obtain the compound of Formula IIA.
The present invention provides a process for the preparation of (R)-2-(2,5- difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl) butan-2-ol, compound of Formula III,
Figure imgf000006_0002
Formula III
the process includes the steps of; a) adding 1,2,4-triazole with trimethylsulfoxonium iodide in a aprotic solvent, b) contacting the solution of (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2- yloxy)propan-l-one in aprotic solvent with the reaction mixture of step a), c) isolating (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)- 1-( 1H- l,2,4-triazol-l-yl)butan-2-ol from the reaction mixture thereof.
In an aspect, the present invention provides conversion of (R)-2-(2,5-difluorophenyl)-3- (tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol to Isavuconazole, Isavuconazonium and its sulfate or iodide hydrochloride salt.
The present invention provides a process for the preparation of l-(((2R,3S)-2-(2,5- difluorophenyl)-3-methyloxiran-2-yl)methyl)-lH- 1,2,4-triazole, compound of Formula
IV,
Figure imgf000007_0001
Formula IV
the process includes the steps of,
a) dissolving (2R,3R)-2-(2,5-difluorophenyl)- 1-( 1H- 1,2,4-triazol- l-yl)butane-2,3- diol with base in the organic solvent,
b) adding the mesyl chloride in the reaction mixture of step a),
c) contacting aqueous solution of base with the reaction mixture of step b), d) isolating l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1,2,4-triazole from the reaction mixture thereof.
In an aspect, the present invention provides conversion of l-(((2R,3S)-2-(2,5- difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1 ,2,4-triazole to Isavuconazole, Isavuconazonium and its sulfate or iodide hydrochloride salt. Description of the Invention
For purposes of the present invention, the following terms are defined below.
The compound of formula II, IIA, III and IV intermediates and starting materials of the present invention may be prepared and /or 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.
The present invention provides a process for the preparation of Isavuconazole or its pharmaceutical acceptable salt thereof compound of formula I
Figure imgf000008_0001
Formula I
the process includes the steps of;
a) condensing 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoro acetic acid in a halogenated solvent to obtain (R)-l- morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one,
b) reacting (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1 ,4-difluorobenzene in presence of n-hexyl lithium in a solvent to obtain the compound of (R)- l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)propan- 1-one,
c) contacting (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)propan-l- one with 1,2,4-triazole and trimethylsulfoxonium iodide in a aprotic solvent to obtain (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH- 1,2,4- triazol- 1 -yl)butan-2-ol,
d) converting (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)- 1 -( 1H- l,2,4-triazol-l-yl)butan-2-ol in to (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4- triazol- 1 -yl)butane-2,3-diol,
e) reacting (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-diol with mesyl chloride in presence of base in a halogenated solvent to obtain 1- (((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1 ,2,4-triazole, f) converting 1 -(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1,2,4-triazole to Isavuconazole or its pharmaceutical acceptable salt thereof.
In an aspect, the present invention provides a process for the preparation of compound of Formula II
Figure imgf000009_0001
Formula II
wherein the ring X is fluorine, which is substituted at 4 or 5 position at benzene ring, the process includes the step of;
a) condensing 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoro acetic acid in a halogenated solvent to obtain (R)-l- morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one,
b) reacting (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,3- or 1,4-difluorobenzene in presence of n-hexyl lithium in a solvent to obtain the compound of Formula II,
The step a) involves condensing 4-[(R)-2-hydroxypropionyl] morpholine with 1,4- dihydropyran in presence of trifluoroacetic acid to obtain (R)-l-morpholino-2- (tetrahydro-2H-pyran-2-yloxy)propan- 1 -one. The reaction is carried out at temperature in between range of -5°C to 40 °C. The reaction mixture may be stirred for a period of about 15 minutes to 1 hour or more at the same temperature for completion. The reaction of step a) may be carried out in presence of halogenated solvent, wherein halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof.
The quantity of trifluoro acetic 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 temperature in between range of 0°C to 20 °C for a period of 5 minutes to 30 minutes, while controlling the exothermicity of the 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 in a solvent to obtain the compound of Formula II, wherein solvent is selected from the group comprising one or more of ether solvent and hydrocarbon solvent and mixture thereof, ether solvent is selected from the group comprising one or more of tetrahydrofuran and diisopropyl ether; hydrocarbon is selected from the group comprising one or more of hexane and heptane.
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 conducted at temperature in between range of -20°C to 40 °C or at -5°C 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 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
Figure imgf000011_0001
Formula IIA
the process includes the step of;
a) condensing 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid in a halogenated solvent to obtain a (R)-l- morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one,
b) reacting (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,4- difluorobenzene in presence of n-hexyl lithium in a solvent to obtain compound of Formula IIA.
The step a) is carried out at a temperature of about 0 to 15 °C in presence of halogenated, wherein halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof. 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 exothermicity of the reaction. After completion of the reaction, the reaction mixture may be washed with basic solution and subjected to concentration or used directly for further reaction. The step b) of the present invention involves the reacting (R)-l-morpholino-2- (tetrahydro-2H-pyran-2-yloxy)propan- 1 -one with 1,4-difluorobenzene in presence of n- hexyl lithium in a solvent, wherein solvent is selected from the group comprising one or more of tetrahydrofuran, diisopropyl ether, hexane, heptane and mixture thereof.
After completion of the reaction, the reaction mixture may be quenched with 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 an aspect, the present invention provides conversion of compound of formula II and compound of formula IIA to Isavuconazole, Isavuconazonium and its sulfate or iodide hydrochloride salt.
In an aspect, the present invention provides a process for the preparation of (R)-2-(2,5- difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl) butan-2-ol, compound of Formula II,
Figure imgf000012_0001
Formula II
the process includes the steps of;
a) adding 1,2,4-triazole with trimethylsulfoxonium iodide in a aprotic solvent, b) contacting the solution of 2,4-difluoro propiophenone in aprotic solvent with the reaction mixture of step a),
c) isolating (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH- 1,2,4- triazol- 1 -yl)butan-2-ol from the reaction mixture thereof. The 1,2,4-triazole is added with trimethylsulfoxonium iodide in a aprotic solvent at temperature between in range of 10 °C to 30 °C, then base is added to the reaction mixture. The reaction is performed in aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2- pyrrolidone, tetrahydrofuran and mixture thereof.
The base may be selected from the group comprising one or more of organic base and inorganic base, wherein organic base is selected from the group comprising one or more of ammonia, dimethylamine, diethylamine or triethylamine, potassium t- butaoxide; inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
To the above solution, 2,4-difluoro propiophenone solution in aprotic solvent at temperature between in range of 60 °C to 85 °C is added. The aprotic solvent comprises one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane, tetrahydrofuran and N- methyl-2-pyrrolidone, and mixture thereof. After completion of the reaction, the reaction mixture is quenched with water at temperature between in range of 10°C to 20°C and finally extracted with ethyl acetate. The ethyl acetate is removed under reduced pressure to get the (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4- triazol-l-yl) butan-2-ol as light yellowish oil.
In an embodiment of the invention, the step (a) to (c) may be carried out using a one -pot procedure.
After completion of the reaction, the reaction mixture may be subjected for concentration or isolation of solid using suitable known techniques such as recrystallization, stripping off the solvent, anti-solvent technique and the like. After completion of the reaction, the reaction mixture may be quenched with water. The obtained organic layer may be concentrated or subjected for isolation of solid using column chromatography or recrystallization techniques or both.
In particular aspect of present invention (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H- pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol obtained according to process of the invention converted to converted to Isavuconazole or its salt to Isavuconazonium iodide hydrochloride and subsequently Isavuconazonium sulfate.
In another aspect, the present invention provides a process for the preparation of 1- (((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1 ,2,4-triazole, compound of Formula II,
Figure imgf000014_0001
Formula II
the process includes the steps of;
a) dissolving (2R,3R)-2-(2,5-difluorophenyl)- 1-( 1H- 1,2,4-triazol- l-yl)butane-2,3- diol with base in the organic solvent,
b) adding the mesyl chloride in the reaction mixture of step a),
c) contacting the reaction mixture of step b) with base,
d) isolating l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1,2,4-triazole from the reaction mixture thereof.
The (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-diol is dissolved in a organic solvent with base at temperature between in range of 20 °C to 30 °C, followed by drop wise addition of mesyl chloride at temperature between in range of 10 °C to 15 °C. The reaction is stirred for 1 to 2 hour at temperature between in range of 15 °C to 30 °C, wherein organic solvent is selected from the group comprising one or more of chloroform, dichloromethane, dichloroethane, chlorobenzene, carbon tetrachloride and water mixture thereof.
The step (c) of the present invention involves the addition of 10% to 20 % aqueous solution of base in the reaction mixture, followed by stirring the biphasic reaction for period of 2 to 4 hour at temperature between in range of 15 °C to 30 °C.
The base may be selected from the group comprising one or more of organic base and inorganic base, wherein organic base is selected from the group comprising one or more of ammonia, dimethylamine, diethylamine or triethylamine, potassium t-butoxide; inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
Isolation involves the removal of organic solvent by means of distillation under reduced pressure to get the l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran -2-yl)methyl)-lH- 1,2,4-triazole as light yellowish oil.
In an embodiment of the invention, the step (a) to (c) may be carried out using a one -pot procedure.
After completion of the reaction, the reaction mixture may be subjected for concentration or isolation of solid using suitable known techniques such as recrystallization, stripping off the solvent, anti-solvent technique and the like.
After completion of the reaction, the reaction mixture may be quenched quenching agent such as water. The obtained organic layer may be concentrated or subjected for isolation of solid using column chromatography or recrystallization techniques or both. In particular aspect of present invention triazole intermediate obtained l-(((2R,3S)-2- (2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)-lH-l,2,4-triazole according to process of the invention converted to converted to Isavuconazole or its salt to Isavuconazonium iodide hydrochloride and subsequently Isavuconazonium sulfate.
The conversion of propan-l-one intermediate, triazole intermediate and oxirane intermediate to Isavuconazole and subsequently to Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate can be carried out know method, e.g. US 6,300,353; US 6,812,238; IN 2424/MUM/2014; IN 2588/MUM/2014 and IN 3189/MUM/2014.
The process of the present invention is depicted in the following Scheme 1:
Figure imgf000016_0001
Scheme 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: Preparation of (R)-2-hydroxy-l-morpholinopropan-l-one
Charged morpholine (250 g, 2.881 mol) in a solution of methyl (R)-lactate (100 g, 0.9606 mol). The reaction mixture was stirred at temperature 85 °C for 40 hours. The solution of morpholine was evaporated under reduced pressure to get the title compound as pale yellow thick oil.
Yield: 162.0 gm
1H NMR, 5ppm (CDC13-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 (m/z): 160.0 (M+l)
HPLC Purity: > 90 %
Example-2: Preparation of (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan- 1-one
Charged (R)-2-hydroxy-l-morpholinopropan-l-one (160g, 1.005 mol) in dichloromethane. The reaction mixture was cooled at temperature 15°C. Trifluoroactic acid (34.3 gm, 0.3015 mol) was added into the reaction mixture, followed by cooling at temperature 10 °C. The 1 ,4-dihydropyran (110 g, 1.3066 mol) was added into the reaction mixture followed by cooling at temperature 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 solvent was distilled out the under reduced pressure to title compound as pale yellow oil. Yield: 200.0 g
1H NMR, 6ppm (CDC13): 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 (m/z): 244.1 (M+)
HPLC Purity: > 90 %
Example-3: Preparation of (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy) propan- 1 -one
Charged 1,4-difluoro benzene (10.5gm, 0.092 mol) in anhydrous tetrahydrofuran (20 ml). The reaction mixture was cooled at temperature -5 to 0 °C. N-hexyllithium (33% in n- hexane) (36.8 ml, 0.092 mol) was added drop wise into the reaction mixture over period of 10 minutes to the reaction mixture, followed by stirring the reaction mixture for 15 minutes at temperature 0°C. Charged (R)-l-morpholino-2-(tetrahydro-2H-pyran-2- yloxy)propan-l-one (15.0 gm, 0.0616 mol) in anhydrous tetrahydrofuran (40 ml), followed by addition of solution into the reaction mixture drop wise over a 10 minutes at temperature -5 to 0 °C. The reaction mixture was stirred for 120 minutes at temperature 0 °C. After the completion of the reaction, the mixture was quenched with ammonium chloride solution. The reaction mixture was extracted into ethyl acetate, followed washing of organic phase with water and brine solution. The resultant organic phase was dried over anhydrous sodium sulfate, followed by filtration. The solvent was distilled out under vacuum to get crude title compound. The crude product was purified by column using silica gel to afford purified title compound as yellowish oily mass.
Yield: 7.3 gm
Proton NMR in CDC13: identical with published Patent US 6,300,353.
Mass (m/z): 271.2 (M+)
Example-4: The preparation of (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2- yloxy)- 1-( 1H- 1,2,4-triazol- l-yl)butan-2-ol Charged (400 ml) tetrahydrofuran, (500 ml) dimethylformamide, 33.1 gm 1,2,4-triazole and 105.6 gm trimethyl sulfoxonium iodide in a flask. The reaction mixture was cooled at temperature between in range of 8 °C - 10 °C and potassium i-butoxide (102.9 gm) was added lot wise. After addition of potassium t-butoxide reaction mixture was stirred for 1 hour at room temperature. The solution of 2,4-difluoro propiophenone (108.0gm) in dimethylformamide (100 ml) was added drop wise over period of 10 minutes into the reaction mixture. The reaction mixture was further stirred for 40 minutes at room temperature and then heated to temperature between in range of 80°C - 85 °C for 6 hours.
After completion of the reaction, it was cooled to temperature 10°C and quench with water (1.2 L). Aqueous layer was extracted with ethyl acetate (1.2 L). The ethyl acetate was distilled out under reduced pressure. The crude product (140 gm) was purified by column by silica gel to get light yellowish oily of tiled compound.
Yield: 120 gm.
Example-5: The preparation of (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l- yl)butane-2,3-diol
Charge (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol- l-yl)butan-2-ol (100 gm) in methanol (250 ml). The reaction mixture was cooled at temperature 15°C to 20 °C, followed by addition of dilute hydrochloric acid (1L) into the reaction mixture at temperature 25°C to 30°C. The reaction mixture was stirred for 4 hours, followed by addition of toluene (250 ml) to the separated layer. The aqueous layer was collected and pH was adjusted to 8 with sodium carbonate (20 % aqueous solution). The compound was extract in dichloromethane (400 ml), followed by washing with water. The solvent was distilled out to get the titled compound as oil.
Yield: 30 g
Example-6: Preparation of l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2- yl)methyl)- 1H- 1 ,2,4-triazole Charged dichloromethane (400 ml) and (2R,3R)-2-(2,5-difluoro phenyl)-l-(lH-l,2,4- triazol-l-yl)butane-2,3-diol (40 gm) in a round bottom flask. Followed triethylarnine (30 gm) was added drop wise at room temperature. Then reaction mixture was cooled at temperature between in range of 10°C to 15°C and mesyl chloride (21.2 gm) was added drop wise at temperature between in range of 10°C to 15°C to the said reaction mixture. After addition of mesyl chloride reaction was stirred for 1-2 hours at temperature between in range of 15°C to 25°C. After completion of the reaction 10 % aqueous Potassium carbonate solution (400 ml) was added in to the reaction mixture and furhter stirred for 1-2 hours at temperature between in range of 15°C to 25°C. Then dichloromethane layer was separated and dichloromethane was distillation out to get the title compound as light yellowish oily product.
Yield: 33.5 gm
HPLC Purity: > 80 %

Claims

We Claim
1. A process for the preparation of Isavuconazole or its pharmaceutical acceptable salt thereof, compound of formula I
Figure imgf000021_0001
Formula I
the process includes the steps of;
a) condensing 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoro acetic acid in a halogenated solvent to obtain (R)-l-morpholino- 2-(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one,
b) reacting (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,4- difluorobenzene in presence of n-hexyl lithium in a solvent to obtain the compound of (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one, c) contacting (R)-l-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,2,4-triazole and trimethylsulfoxonium iodide in a aprotic solvent to obtain (R)- 2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l- yl)butan-2-ol,
d) converting (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH- 1,2,4- triazol-l-yl)butan-2-ol in to (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l- yl)butane-2,3-diol,
e) reacting (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butane-2,3-diol with mesyl chloride in presence of base in a halogenated solvent to obtain l-(((2R,3S)-2- (2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1 ,2,4-triazole,
f) converting 1 -(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- 1H- 1,2,4-triazole to Isavuconazole or its pharmaceutical acceptable salt thereof.
2. The process of claim 1, wherein halogenated solvent is selected from the group comprising one or more of dichlorome thane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof.
3. The process of claim 1 , wherein halogenated solvent is dichloromethane. 4. The process of claim 1, wherein solvent is selected from the group comprising one or more of tetrahydrofuran, diisopropyl ether, hexane, heptane and mixture thereof.
5. The process of claim 4, wherein solvent is tetrahydrofuran. 6. The process of claim 1, wherein base comprises one or more of organic base and inorganic base.
7. The process of claim 6, wherein organic base is selected from the group comprising one or more of dimethylamine, diethylamine, ammonia, potassium i-butoxide and triethylamine.
8. The process of claim 6, wherein inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
9. The process of claim 1 , wherein Isavuconazole can be converted Isavuconazonium or its pharmaceutical acceptable salt thereof. 10. A process for the preparation com ound of Formula II
Figure imgf000022_0001
Formula II wherein the ring X is fluorine, which is substituted at 4 or 5 position at benzene ring, the process comprises the step of;
a) condensing of 4-[(R)-2-hydroxypropionyl] morpholine with 1 ,4-dihydropyran in presence of trifluoroacetic acid in a halogenated solvent to obtain (R)-l- morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one,
b) reacting (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,3- or 1,4-difluorobenzene in presence of n-hexyl lithium in a solvent to obtain the compound of Formula II,
11. The process of claim 10, wherein halogenated solvent is selected from the group comprising one or more of dichloromethane, chloroform, chlorobenzene, carbon tetrachloride and mixture thereof.
12. The process of claim 10, wherein the quantity of trifluoroacetic acid is about 0.1 to 1 molar equivalents per equivalent of 4-[(R)-2-hydroxypropionyl] morpholine.
13. The process of claim 10, wherein solvent is selected from the group comprising one or more of tetrahydrofuran, diisopropyl ether, hexane, heptane and mixture thereof.
14. The process of claim 10, wherein is compound of Formula II converted to Isavuconazole and Isavuconazonium.
15. A process for the preparation of com ound of Formula IIA
Figure imgf000023_0001
Formula IIA
the process comprises the step of ; a) condensing 4-[(R)-2-hydroxypropionyl] morpholine with 1,4-dihydropyran in presence of trifluoroacetic acid in a dichloromethane solvent to obtain 4 (R)-l- morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan- 1 -one,
b) reacting (R)-l-morpholino-2-(tetrahydro-2H-pyran-2-yloxy)propan-l-one with 1,4-difluorobenzene in presence of n-hexyl lithium in a solvent to obtain the compound of Formula IIA.
The process of claim 15, wherein is compound of Formula IIA converted Isavuconazole and Isavuconazonium.
A process for the preparation of (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran yloxy)-l-(lH-l,2,4-triazol- -yl)butan-2-ol compound of Formula III,
Figure imgf000024_0001
Formula III
the process comprises the steps of;
a) adding 1,2,4-triazole with trimethylsulfoxonium iodide in a aprotic solvent, b) contacting the solution of 2,4-difluoro propiophenone in aprotic solvent with the reaction mixture of step (a),
c) isolating (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4- triazol-l-yl)butan-2-ol from the reaction mixture thereof.
The process of claim 17, wherein aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2- pyrrolidone, tetrahydrofuran and mixture thereof. The process of claim 18, wherein aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide, tetrahydrofuran and mixture thereof.
The process of claim 17, wherein step (a) is carried out in presence of base.
The process of claim 20, wherein base comprises one or more of organic base and inorganic base.
22. The process of claim 21 , wherein organic base is selected from the group comprising one or more of dimethylamine, diethylamine, ammonia, potassium t-butoxide and triethylamine.
The process of claim 21, wherein inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
The process of claim 17, wherein (R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2- yloxy)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol is converted to Isavuconazole and Isavuconazonium.
A process for the preparation of l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran -2- yl)methyl)-lH-l,2,4-triazole, compound of Formula IV,
Figure imgf000025_0001
Formula IV
the process comprises the step of
a) dissolving (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl) butane-2,3- diol with base in a halogenated solvent, b) adding the mesyl chloride in the reaction mixture of step a),
c) contacting the reaction mixture of step b) with base,
d) isolating 1 -(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2-yl)methyl)- lH-l,2,4-triazole from the reaction mixture thereof.
26. The process of claim 25, wherein halogenated solvent is selected from the group comprising one or more of chloroform, dichlorome thane, dichloroethane, chlorobenzene, carbon tetrachloride and water mixture thereof.
27. The process of claim 25, wherein base comprises one or more of organic base and inorganic base.
28. The process of claim 27, wherein organic base is selected from the group comprising one or more of dimethylamine, diethylamine, ammonia, potassium t-butoxide and triethylamine.
29. The process of claim 27, wherein inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
30. The process of claim 25, wherein (l-(((2R,3S)-2-(2,5-difluorophenyl)-3-methyloxiran-2- yl)methyl)-lH-l,2,4-triazole is converted to Isavuconazole or its salt to Isavuconazonium iodide hydrochloride and subsequently Isavuconazonium sulfate.
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JP2018533635A (en) * 2015-11-17 2018-11-15 ダウ アグロサイエンシィズ エルエルシー 4-((6- (2- (2,4-Difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) pyridine -3-yl) oxy) benzonitrile and method of preparation
JP2018538366A (en) * 2015-11-17 2018-12-27 ダウ アグロサイエンシィズ エルエルシー 4-((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl) pyridine-3 -Yl) oxy) benzonitrile and preparation method
CN105777740A (en) * 2016-02-24 2016-07-20 刘可 Preparation method of isavuconazole and isavuconazole prepared through method
CN115536643A (en) * 2022-12-05 2022-12-30 南京桦冠生物技术有限公司 Preparation method of key intermediate of isavuconazole medicine
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