DESC:FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003

COMPLETE SPECIFICATION
(SECTION 10 and rule 13)

“PROCESS FOR THE PREPARATION OF ISAVUCONAZONIUM SULFATE”

Glenmark Life Sciences Limited
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO – Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai – 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
[0001] The present invention relates to process for preparation of isavuconazonium sulfate.
BACKGROUND OF THE INVENTION
[0002] Isavuconazonium sulfate is chemically known as Glycine, N-methyl-, [2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxy butyl]-4H-1, 2, 4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester, sulfate (1:1).
[0003] Isavuconazonium sulfate marketed as CRESEMBA® is a capsule for oral administration. Isavuconazonium sulfate is also marketed as CRESEMBA® for injection for intravenous administration.
[0004] The present invention provides novel process for preparation of isavuconazonium sulfate which provides better purity profile and which can be easily performed on industrial scale.
SUMMARY OF THE INVENTION
[0005] In one embodiment, the present invention provides a process for the preparation of isavuconazonium sulfate, a compound of formula I
I
comprising:
a) reacting a compound of formula II, with a compound of formula III in the presence of methanol to obtain a reaction mixture containing isavuconazole, a compound of formula IV;

II III IV
b) reacting isavuconazole, the compound of formula IV obtained from the above reaction mixture with an ester of formula V

V
in the presence of an iodide source to obtain N-Boc isavuconazonium iodide;
c) converting the N-Boc isavuconazonium iodide to N-Boc isavuconazonium chloride;
d) purifying the obtained N-Boc isavuconazonium chloride by treatment with a solvent system comprising a mixture of methanol, water and toluene to obtain N-Boc isavuconazonium chloride with a purity of at least 95%; and
e) converting N-Boc isavuconazonium chloride to isavuconazonium sulfate.
DETAILED DESCRIPTION OF THE INVENTION
[0006] In one embodiment, the present invention provides a process for the preparation of isavuconazonium sulfate, a compound of formula I
I
comprising:
a) reacting a compound of formula II, with a compound of formula III in the presence of methanol to obtain a reaction mixture containing isavuconazole, a compound of formula IV;

II III IV
b) reacting isavuconazole, the compound of formula IV obtained from the above reaction mixture with an ester of formula V

V
in the presence of an iodide source to obtain N-Boc isavuconazonium iodide;
c) converting N-Boc isavuconazonium iodide to N-Boc isavuconazonium chloride;
d) purifying the obtained N-Boc isavuconazonium chloride by treatment with a solvent system comprising a mixture of methanol, water and toluene to obtain N-Boc isavuconazonium chloride with a purity of at least 95%; and
e) converting N-Boc isavuconazonium chloride to isavuconazonium sulfate.
[0007] In one embodiment, in step a), the compound of formula II is reacted with the compound of formula III in methanol to obtain a reaction mixture.
[0008] The reaction is carried at a temperature of about 20°C to about reflux temperature of the solvent. Preferably the reaction is carried out at a temperature of about 45°C to about 70°C.
[0009] In one embodiment, the reaction mixture containing isavuconazole, the compound of formula IV, is subjected to basification by a process comprising the step of adjusting the pH of the reaction mixture containing isavuconazole to about 7 to about 8 at a temperature of about above 50°C.
[0010] In one embodiment, it was surprisingly noted that when the reaction mixture containing isavuconazole, the compound of formula IV, is subjected to basification by a process comprising the step of adjusting the pH of the reaction mixture containing isavuconazole to about 7 to about 8 at a temperature above 50°C there are no lump formation in the reaction mixture.
[0011] In one embodiment, the reaction mixture containing isavuconazole, the compound of formula IV, is subjected to basification by a process comprising the step of adjusting the pH of the reaction mixture containing isavuconazole to about 7 to about 8 at a temperature of about 50°C to about 60°C.
[0012] In one embodiment, isavuconazole from the reaction mixture is further isolated by a process comprising:
i) extracting isavuconazole from the reaction mixture by addition of methanol to obtain a methanolic solution comprising isavuconazole;
ii) heating the methanolic solution comprising isavuconazole;
iii) adding water to the methanolic solution of above step ii) to obtain an aqueous methanolic solution comprising isavuconazole;
iv) cooling the above aqueous methanolic solution comprising isavuconazole; and
v) isolating isavuconazole.
[0013] In one embodiment, step ii) of the above process involves heating the methanolic solution comprising isavuconazole to a temperature of about 50°C.
[0014] In one embodiment, step ii) of the above process involves heating the methanolic solution comprising isavuconazole to a temperature of about 50°C to about 55°C.
[0015] In one embodiment, step iii) of the above process involves addition of water to the above methanolic solution of step ii) to obtain an aqueous methanolic solution comprising isavuconazole.
[0016] In one embodiment, step iv) of the above process involves cooling the aqueous methanolic solution comprising isavuconazole to a temperature of about below 25°C. Preferably the solution is cooled to a temperature between 10°C to about 20°C.
[0017] In one embodiment, in step iv), the aqueous methanolic solution comprising isavuconazole is maintained at a temperature between about 10°C to about 20°C to precipitate isavuconazole for a period of about 18 to about 50 hours.
[0018] In one embodiment, in step iv), the aqueous methanolic solution comprising isavuconazole is seeded to precipitate isavuconazole. The precipitated isavuconazole is isolated by methods known in the art such as filtration, centrifugation and the like.
[0019] In one embodiment, the isolated isavuconazole is further purified in a mixture of water and methanol to obtain isavuconazole, the compound of formula IV, in a purity of at least 99% as measured by HPLC.
[0020] In one embodiment, it was surprisingly found that the preparation and purification of isavuconazole, the compound of formula IV, in a single organic solvent methanol eliminates the dimer impurity of formula VI

VI.
[0021] In one embodiment, the dimer compound is characterized by 1HNMR having peaks at 9.884, 8.832, 8.493, 8.249-8.229, 8.180-8.123, 7.965-7.946, 7.382-7.361, 7.272, 7.137-7.125, 6.617, 6.059-6.043, 5.152-5.116, 4.898-4.861, 4.224-4.206 1.237-1.220.
[0022] In one embodiment, the dimer compound is characterized by IR Spectrum (KBr)cm-1 having peaks at 3651.12, 3383.94, 3127.08, 2989.47, 2227.94, 1704.93, 1607.08, 1572.94, 1527.05, 1489.52, 1437.35, 1405.04, 1354.71, 1294.03, 1265.07, 1237.29, 1166.53, 1138.27, 1092.70, 1074.66, 1062.35, 997.81, 930.91, 894.00, 874.26, 854.75, 830.15, 755.97, 725.95, 702.94, 626.39, 575.84, 548.67.
[0023] In one embodiment, in step a), isavuconazole, the compound of formula IV, is obtained by a process, wherein the reaction solvent and the work-up solvent involves use of single organic solvent.
[0024] In one embodiment, in step a), isavuconazole, the compound of formula IV, is obtained by a process, wherein the reaction solvent and the work-up solvent involves use of single organic solvent and optionally water as a co-solvent in the work-up process.
[0025] In one embodiment, the organic solvent may be selected from the group consisting of C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; ether like diethyl ether, methyl tertiary butyl ether and the like; amides such as dimethyl formamide, dimethyl acetamide and the like. Preferably, the solvent is methanol.
[0026] In one embodiment, step a) involves reaction of compound of formula II with the compound of formula III to obtain isavuconazole, the compound of formula IV, in methanol as the organic solvent wherein the process of work-up of reaction mixture comprising isavuconazole involves use of methanol as the single organic solvent.
[0027] The use of single organic solvent such as methanol in both reaction and work-up results in a cost effective process.
[0028] In one embodiment, the present invention provides a process for preparation of isavuconazole in a purity of at least 99% as measured by HPLC and wherein the content of dimer impurity, the compound of formula VI, is less than 0.3% as measured by HPLC.
[0029] In one embodiment, in step b), isavuconazole, the compound of formula IV, obtained from the above reaction mixture is reacted with an ester of formula V in the presence of an iodide source to obtain N-Boc isavuconazonium iodide.
[0030] In one embodiment, the suitable iodide source may be selected from the group consisting of trimethylsilyl iodide, hydrogen iodide, sodium iodide or potassium iodide. Preferably, the suitable iodide source is sodium iodide.
[0031] In one embodiment, sodium iodide is added as a solution into the reaction mixture comprising of isavuconazole, the compound of formula IV and the ester of compound of formula V in a suitable solvent.
[0032] The solvent may be selected from the group consisting of a ketone solvent such as acetone, methyl ethyl ketone, isopropyl ketone, methyl tert-butyl ketone and the like; a hydrocarbon solvent selected from the group consisting of toluene, xylene, cyclohexane, n-heptane, hexane and the like; a halogenated hydrocarbon solvent selected from the group consisting of methylene dichloride, ethylene dichloride, chloroform and the like; an amide solvent selected from the group consisting of dimethyl formamide, dimethyl acetamide, formamide and the like; sulfoxide such as dimethyl sulfoxide and the like; an ether solvent selected from the group consisting of diethyl ether, di-isopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; an ester solvent selected from the group consisting of ethyl acetate, butyl acetate, isopropyl acetate and the like; a nitrile solvent such as acetonitrile, propionitrile, C1-C5 alcohol selected from the group consisting of methanol, ethanol, propanol, butanol, isopropanol and the like. Preferably the solvent is acetonitrile
[0033] In one embodiment, isavuconazole, a compound of formula IV is reacted with an ester of formula V in the presence of sodium iodide in acetonitrile to obtain an intermediate compound N-Boc isavuconazonium iodide, wherein sodium iodide is added as a solution to a mixture comprising isavuconazole, the compound of formula IV and the ester, the compound of formula V.
[0034] In one embodiment, the solvent is as discussed supra.
[0035] In one embodiment, in step c), N-Boc isavuconazonium iodide is converted to N-Boc isavuconazonium chloride using a pressure column containing chloride resin.
In one embodiment, the use of a pressure column in conversion of N-Boc isavuconazonium iodide to N-Boc isavuconazonium chloride provides the N-Boc isavuconazonium chloride to be obtained in constant yield.
[0036] In one embodiment, in step d), the N-Boc isavuconazonium chloride is purified by treatment with a solvent system comprising a mixture of methanol, water and toluene to obtain N-Boc isavuconazonium chloride with a purity of at least 95%.
[0037] In one embodiment, the solvent system comprising a mixture of methanol, water and toluene in above step d) eliminates any unreacted isavuconazole from the reaction mixture, thereby increasing the purity of N-Boc isavuconazonium chloride.
[0038] In one embodiment, in step d), N-Boc isavuconazonium chloride is purified by treatment with a solvent system comprising a mixture of methanol, water and toluene wherein isavuconazole, the compound of formula IV, to the solvent system ratio (g/ml) is about 1:25 to about 1:50 to obtain N-Boc isavuconazonium chloride with a purity of at least 95%.
[0039] In one embodiment, the solvent system comprising methanol, water and toluene are in a ratio of about 0.5:0.5:0.75 to about 1.5:1.5:3.0 (v/v).
[0040] In one embodiment, in step d), N- Boc isavuconazonium chloride is purified in a solvent system comprising a mixture of methanol, water and toluene wherein isavuconazole, the compound of formula IV, to solvent system ratio (g/ml) is about 1:35.
[0041] In one embodiment, in step d), the solvent system comprising methanol, water and toluene are in ratio of about 1:1:1.5 (v/v).
[0042] In one embodiment, the term “treatment” refers to washing, slurring, crystallizing or leaching N-Boc isavuconazonium chloride in the solvent system comprising methanol, water and toluene.
[0043] In one embodiment, the process of purification of N-Boc isavuconazonium chloride by treatments refers to preparing a solution of N-Boc isavuconazonium chloride in methanol and washing with a mixture of water and toluene.
[0044] In one embodiment, the process of purification N-Boc isavuconazonium chloride refers to preparing a solution of N-Boc isavuconazonium chloride in methanol and washing with a mixture of water and toluene wherein, the isavuconazole, the compound of formula IV, to solvent system ratio (g/ml) is about 1:25 to about 1:50 and the solvents are in a ratio of about 0.5:0.5:0.75 to about 1.5:1.5:3.0 (v/v).
[0045] In one embodiment, the N-Boc isavuconazonium chloride purified from a solvent system comprising methanol, water and toluene, is having a purity of at least 97% as measured by HPLC.
[0046] In one embodiment, N-Boc isavuconazonium chloride is isolated as a solid by a process comprising:
i) removing the solvent from a solution comprising N-Boc isavuconazonium chloride to obtain a residue;
ii) contacting the residue with a mixture of ester and a hydrocarbon solvent to precipitate N-Boc isavuconazonium chloride; and
iii) isolating N-Boc isavuconazonium chloride.
[0047] In one embodiment, above step i) involves removal of the solvent from a solution comprising N-Boc isavuconazonium chloride, wherein the solvent is a mixture comprising methanol, water and toluene by process known in the art such as distillation to obtain a residue.
[0048] In one embodiment, step ii) of the above process involves contacting the above residue with a mixture of ester and a hydrocarbon solvent.
[0049] In one embodiment, the ester is selected from the group consisting of ethyl acetate, isopropyl acetate and the like; hydrocarbon solvent is selected from the group consisting of toluene, heptane, xylene, cyclohexane and the like.
[0050] In one embodiment, step ii) of the above process involves contacting the residue containing N-Boc isavuconazonium chloride with a mixture of ethyl acetate and n-heptane to precipitate N-Boc isavuconazonium chloride.
[0051] In one embodiment, step iii) of the above process involves isolation by methods such as filtration, centrifugation and the like.
[0052] In one embodiment, step ii) of the above process involves isolating N-Boc isavuconazonium chloride from a solvent mixture of ethyl acetate and n-heptane.
[0053] In one embodiment, in step e), the conversion of N-Boc isavuconazonium chloride to isavuconazonium sulfate comprises:
i) treating N-Boc isavuconazonium chloride with hydrochloric acid to generate isavuconazonium chloride hydrochloride; and
ii) dissolving isavuconazonium chloride hydrochloride in water and treating with sulfate containing anion exchange resin to obtain isavuconazonium sulfate.
[0054] In one embodiment, in step i) of the above process N-Boc isavuconazonium chloride, is reacted with hydrochloric acid to generate isavuconazonium chloride hydrochloride in a suitable solvent.
[0055] The suitable solvent may be selected from the group consisting of C1-C5 alcohol, ketone, hydrocarbon, halogenated hydrocarbon, amide, sulfoxide, ether, ester, nitrile, water and mixtures thereof.
[0056] In one embodiment, the hydrochloric acid used may be commercially available hydrochloric acid or can be passed as a hydrochloride gas or hydrochloride gas in any organic solvent, or aqueous hydrochloric acid.
[0057] In one embodiment, the alcohol solvent may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, cyclohexanol and the like; ketone solvent may be selected from the group consisting of acetone, methyl ethyl ketone, isopropyl ketone, methyl tert-butyl ketone and the like; hydrocarbon solvent may be selected from the group consisting of toluene, xylene, cyclohexane, n-heptane, hexane and the like; halogenated hydrocarbon solvent may be selected from the group consisting of methylene dichloride, ethylene dichloride, chloroform and the like; amide solvent may be selected from the group consisting of dimethyl formamide, dimethyl acetamide, formamide and the like; sulfoxide such as dimethyl sulfoxide and the like; an ether solvent may be selected from the group consisting of diethyl ether, di-isopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; an ester solvent may be selected from the group consisting of ethyl acetate, butyl acetate, isopropyl acetate and the like; nitrile may be selected from the group consisting of acetonitrile, propionitrile and the like.
[0058] In one embodiment, N-Boc isavuconazonium chloride in ethyl acetate is reacted with hydrochloric acid in ethyl acetate to obtain isavuconazonium chloride hydrochloride in an ethyl acetate solution.
[0059] In one embodiment, isavuconazonium chloride hydrochloride is generated in- situ on reaction of N-Boc isavuconazonium chloride with hydrochloric acid.
[0060] The term “in-situ” means the intermediates formed in the steps referred to are not isolated. The term “not isolated” means the intermediates referred to are not separated as a solid.
[0061] In one embodiment, the term “in-situ” means the process of the invention is carried out without isolation of isavuconazonium chloride hydrochloride in the form of a solid compound.
[0062] In one embodiment, the generated isavuconazonium chloride hydrochloride in ethyl acetate solution is exchanged with water to obtain an aqueous solution containing isavuconazonium chloride hydrochloride.
[0063] In one embodiment, the obtained aqueous solution containing isavuconazonium chloride hydrochloride is subjected to treatment with a solvent mixture of C1-C4 alcohol and halogenated hydrocarbon.
[0064] In one embodiment, the C1-C4 alcohol may be selected from the group consisting of methanol, ethanol, isopropanol, propanol, n-butanol and the like; the halogenated hydrocarbon may be selected from the group consisting of methylene dichloride, ethylene dichloride and the like.
[0065] In one embodiment, the aqueous solution containing isavuconazonium chloride hydrochloride is subjected to treatment with a solvent mixture of ethyl acetate and methylene dichloride.
[0066] In one embodiment, the aqueous solution containing isavuconazonium chloride hydrochloride is treated with sulfate containing anion exchange resin to obtain isavuconazonium sulfate.
[0067] In one embodiment, the isavuconazonium chloride hydrochloride obtained in above step i) is not isolated and contacted in situ with sulfate containing anion exchange resin to obtain isavuconazonium sulfate.
[0068] In one embodiment, the isavuconazonium chloride hydrochloride is converted to isavuconazonium sulfate using a pressure column containing sulfate resin to obtain isavuconazonium sulfate.
[0069] In one embodiment, isavuconazonium sulfate is subjected to treatment with a solvent mixture of C1-C4 alcohol and halogenated hydrocarbon.
[0070] In one embodiment, the C1-C4 alcohol and halogenated hydrocarbon solvent is as discussed supra.
[0071] In one embodiment, isavuconazonium sulfate is subjected to treatment with a solvent mixture of n-butanol and methylene dichloride to obtain isavuconazonium sulfate in a purity of at least 96% as measured by HPLC.
[0072] In one embodiment, the obtained isavuconazonium sulfate is subjected to treatment with a solvent mixture of n-butanol and methylene dichloride wherein the content of isavuconazole, the compound of formula IV and /or content of the compound of formula VII
IV VII
in the obtained isavuconazonium sulfate is less than 0.5% w/w with respect to isavuconazonium sulfate as measured by HPLC.
[0073] In one embodiment, the present invention provides amorphous isavuconazonium sulfate.
[0074] In one embodiment, the amorphous isavuconazonium sulfate obtained by the present invention has a chemical purity of at least 95%.
[0075] In one embodiment, the amorphous isavuconazonium sulfate obtained by the present invention has a chemical purity of at least 96%.
[0076] In one embodiment, the amorphous isavuconazonium sulfate obtained by the present invention has a chiral purity of at least 90%.
[0077] In one embodiment, the amorphous isavuconazonium sulfate obtained by the present invention has a chiral purity of at least 95%.
[0078] In one embodiment, the amorphous isavuconazonium sulfate obtained by the present invention has a chiral purity of at least 99%.
[0079] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

Examples:
Example-1 :- 4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile :-
To (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanethioamide(100g) in 500mL methanol was added 4-(bromoacetyl)benzonitrile(75g). Reaction mass was heated to 55-65°C. After completion of reaction, pH of reaction mass adjusted to about 7.0 at 50-65°C. The layers were separated at a temperature of about 55°C to about 60°C. The oily layer was dissolved in 400mL methanol and the obtained solution was heated to temperature of about 55°C to about 65°C followed by addition of 1.5 volume of water. The reaction mass was cooled to temperature of about 20°C to about 30°C. The solution was seeded with standard compound. The reaction mass was cooled to temperature of about 15°C to about 20°C and stirred for 8 hours. The solid was filtered and washed with a mixture of methanol and water. Purity by HPLC: 97.57%, Dimer impurity: 1.75%, other isomer: 0.34%
The obtained wet cake was stirred in mixture of methanol and water (4:1.5) at a temperature of about 55°C to about 65°C. The reaction mass was cooled to about 20°C to about 30°C and stirred for 6 hours. The precipitated solid was filtered and solid washed with a mixture of methanol and water. The product was dried in vacuum tray drier. Purity by HPLC: 99.7%, Dimer impurity: 0.11%,

Example 2: Preparation of (2-{[(1-{1-[(2R, 3R)-3-[4-(4-cyanophenyl)-1, 3-thiazol-2-
yl]-2-(2, 5-difluorophenyl)-2-hydroxybutyl]-1H-1, 2, 4-triazol-4-ium-4-
yl} ethoxy) carbonyl] (methyl) amino} pyridin-3-yl) methyl-N-(tert-butoxycarbonyl)-N-methylglycinate chloride:-
4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile(100g) was suspended in acetonitrile (750mL) and to this was added (2-{[(1-chloroethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate (114.07g). The reaction mass was heated to a temperature of about 50°C to about 55°C. A solution of sodium iodide (41.11g) in acetonitrile (650ml) was added and the reaction mass was maintained for about 15 hours at a temperature of about 50°C to about 55°C. The reaction mass was filtered and distilled completely under vacuum. The obtained residue was dissolved in methanol (700ml) and was passed through resin SA10A (chloride) and resin SA10A (chloride) was washed with methanol (300ml). The obtained solution contained product.
Purity by HPLC: 82.41%, content of isavuconazole, compd IV: 13.5%, content of ester compd V: 0.54%
To the above obtained solution water (1000ml) and toluene (1500ml) were added. The layers were separated and the aqueous layer was washed with toluene followed by extraction of the aqueous layer with methylene dichloride (MDC).The MDC layer was distilled and residue was dissolved in ethyl acetate (400ml) and to this n-heptane (1000mL) was added to precipitated product at a temperature of about -5°C to about 0°C.The precipitated product was filtered and dried at 45-50°C under vacuum to obtain 130g of title product. Purity by HPLC: 98%, content of isavuconazole, compd IV: 0.17%, content of ester compd V: 0.25%

Example 3: Preparation of (2-{[(1-{1-[(2R, 3R)-3-[4-(4-cyanophenyl)-1, 3-thiazol-2-
yl]-2-(2, 5-difluorophenyl)-2-hydroxybutyl]-1H-1, 2, 4-triazol-4-ium-4-yl} ethoxy)
carbonyl] (methyl) amino} pyridin-3-yl) methyl-N-methylglycinate Sulfonium salt:
(2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl) Methyl N-(tert-butoxycarbonyl)-N-methylglycinate chloride (5g) was suspended in ethyl acetate (75mL). The reaction mass was cooled to a temperature of about 15°C to about 20°C. To this reaction mass a solution of hydrochloric acid in ethyl acetate (25g) was added. The reaction mass was warmed to a temperature of about 25°C to about 30°C. On completion of reaction, hyflow was added to the reaction mass. The reaction mass was filtered and the hyflo bed washed with ethyl acetate. To the hyflo bed containing product a mixture of ethyl acetate and water were added. This slurry was filtered. The layers of the filtrate were separated. The aqueous layer containing product was washed with a mixture of n-butanol and methylene dichloride and the aqueous layer was passed through sulfate containing anion exchange resin to obtain the product in the eluted aqueous layer. Purity by HPLC: 87.38%
Content of isavuconazole, IV: 2.01%%
Content of impurity ester, V : 0.27%
Content of impurity at RRT 1.28:7.52%
The aqueous layer containing product was washed with mixture of n-butanol and methylene dichloride. The aqueous layer was washed again with cyclohexane. The obtained aqueous layer was lyophilized to obtain 2.5g of amorphous Isavuconazonium sulfate. Purity by HPLC: 98.13%, content of isavuconazole (IV):0.15%, content of ester (V): Not detected; content of impurity at RRT 1.28:0.42%,
Comparative example:
Preparation of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl] (methyl)amino}pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate chloride:
4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile(10g) was suspended in acetonitrile (70mL). A solution of (2-{[(1-chloroethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate(12.36g) in acetonitrile (30mL) and sodium iodide(4.56g) was added to the above suspension. The reaction mass was heated to 50-55°C for about 15 hours. The reaction mass was filtered and distilled completely under vacuum. The obtained residue was dissolved in aqueous methanol filtered through celite and the filtrate was passed through resin SA10A (chloride). The obtained solution containing product was distilled under vacuum. The residue was dissolved in ethyl acetate and washed with water. The ethyl acetate layer was distilled under vacuum. The residue was slurried in n-hexane. The precipitated product was filtered and dried at 45-50°C under vacuum to obtain 14g of title product. Purity > 85%.
,CLAIMS:We claim:
1] A process for the preparation of isavuconazonium sulfate, a compound of formula I
I
comprising:
a) reacting a compound of formula II, with a compound of formula III in the presence of methanol to obtain a reaction mixture containing isavuconazole, a compound of formula IV;

II III IV
b) reacting isavuconazole, the compound of formula IV obtained from the above reaction mixture with an ester of formula V

V
in the presence of an iodide source to obtain N-Boc isavuconazonium iodide;
c) converting the N-Boc isavuconazonium iodide to N-Boc isavuconazonium chloride;
d) purifying the obtained N-Boc isavuconazonium chloride by treatment with a solvent system comprising a mixture of methanol, water and toluene to obtain N-Boc isavuconazonium chloride with a purity of at least 95%; and
e) converting the N-Boc isavuconazonium chloride to isavuconazonium sulfate.

2] The process as claimed in Claim 1, wherein in step a), the isolated isavuconazole is further purified in a mixture of water and methanol to obtain isavuconazole, the compound of formula IV, in a purity of at least 99% as measured by HPLC.

3] The process as claimed in Claim 1, wherein in step c), N-Boc isavuconazonium iodide is converted to N-Boc isavuconazonium chloride using a pressure column containing chloride resin to obtain N-Boc isavuconazonium chloride.
4] The process as claimed in Claim 1, wherein in step d), N-Boc isavuconazonium chloride is purified by treatment with a solvent system comprising a mixture of methanol-water-toluene wherein isavuconazole, the compound of formula IV, to solvent system ratio (g/ml) is about 1:25 to about 1:50 to obtain N-Boc isavuconazonium chloride with a purity of at least 95%.
5] The process as claimed in Claim 1, wherein in step d), N-Boc isavuconazonium chloride is isolated from a solvent mixture of ethyl acetate and n-heptane.
6] The process as claimed in Claim 1, wherein in step e), the conversion of N-Boc isavuconazonium chloride to isavuconazonium sulfate comprises:
i) treating N-Boc isavuconazonium chloride with hydrochloric acid to generate isavuconazonium chloride hydrochloride;
ii) dissolving isavuconazonium chloride hydrochloride in water and treating with anion exchange resin to obtain isavuconazonium sulfate.

7] The process as claimed in Claim 6, wherein in step ii), the obtained isavuconazonium sulfate is further treated with a mixture of n-butanol and methylene dichloride to obtain isavuconazonium sulfate with a purity of at least 96% as measured by HPLC.

8] The process as claimed in Claim 6, wherein the content of isavuconazole, the compound of formula IV, and /or content of the compound of formula VII
IV VII
in the obtained isavuconazonium sulfate is less than 0.5% w/w with respect to isavuconazonium sulfate as measured by HPLC.

Dated this 10th day of September, 2019