PROCESS FOR THE PREPARATION SALTS OF TRIAZOLE COMPOUNDS

Abstract

The present invention discloses a large scale process for preparation of triazole compounds using polar and non-polar solvents. More particularly relates to s method of preparing dilauryl glyceryl fumarate salt of posaconazole, voriconazole and itraconazole respectively. The method comprises of dissolving triazole compound and dilauryl glyceryl fumarate in a suitable polar solvent at a temperature range of 30-55° C. for salt formation and final salt is isolated using non-polar solvent at a low temperature range of 0-35° C. It further discloses a method of producing fine particulate size of the dilauryl glyceryl fumarate salt of triazole preferably in the size ranging from 0.001 micron to 100 micron. It also discloses a method of preparing a desired pharmaceutical preparation.

Claims

1. A process for preparation of triazole salts comprises of: a. the salt formation; by dissolving a triazole compound and a dilaurylglyceryl fumarate in a suitable polar solvents for formation of a triazole salt at a pre-determined temperate and time; and b. isolation of the triazole salt using a non-polar cyclic or acyclic hydrocarbon solvent; wherein the polar solvent for salt formation is selected from polar protic solvents or polar aprotic solvents; further the non-polar solvent for isolation of the triazole salt is selected from cyclic and acyclic hydrocarbons.

2. The process of claim 1, wherein the triazole compounds are posaconazole, voriconazole and itraconazole.

3. The process of claim 1, wherein the polar protic solvents and polar aprotic solvents for salt formation comprises methanol, ethanol, isopropanol, water, acetonitrile, methyl tertiary butyl ether (MTBE), tetrahydrofuran, chlorinated solvent, dichloromethane, teracholoethane or chloroform preferably acetonitrile and dichloromethane.

4. The process of claim 1, wherein, the non-polar cyclic or acyclic hydrocarbon solvent for isolation comprises cyclohexane, hexane or heptane preferably hexane.

5. The process of claim 1, wherein, the triazole salt are isolated in the form of amorphous salt, crystalline salt or a combination.

6. The process of claim 1, wherein the triazole salts are selected from a group consisting of dilauryl glyceryl fumarate of posaconazole, dilauryl glyceryl fumarate of voriconazole and dilauryl glyceryl fumarate of itraconazole.

7. The process according to claim 1, wherein the preparation of dilauryl glyceryl fumarate of posaconazole comprises of: a. dissolving posaconazole and dilaurylglyceryl fumarate in the acetonitrile and heating the reaction mixture to a temperature about 50-55° C. for 180 minutes with continuous stirring to obtain a clear solution; b. acetonitrile is distilled off from the reaction mixture at temperature not exceeding 40° C. to obtain a solid having the dilauryl glyceryl fumarate of posaconazole; and c. dilauryl glyceryl fumarate of posaconazole is isolated from the solid of step b by washing and filtering the solid in hexane to yield above 97.3% dilauryl glyceryl fumarate of posaconazole a solid.

8. The process as claimed in claim 1, wherein the preparation of dilauryl glyceryl fumarate of voriconazole comprises of: a. dissolving voriconazole and dilaurylglyceryl fumarate in the acetonitrile and heating the reaction mixture to a temperature about 50-55° C. for 180 minutes with continuous stirring to obtain a clear solutions; b. acetonitrile is distilled off from the reaction mixture at temperature not exceeding 40° C. to obtain a solid mixture having the dilauryl glyceryl fumarate of voriconazole; and c. dilauryl glyceryl fumarate of voriconazole is isolated from the solid mixture by washing, filtering drying the solid mixture in hexane to yield above 98.8% dilauryl glyceryl fumarate of voriconazole as a solid.

9. The process as claimed in claim 1, wherein the preparation of dilauryl glyceryl fumarate of itraconazole comprises of: a. dissolving itraconazole and dilaurylglyceryl fumarate in the dichloromethane and heating the reaction mixture to a temperature about 35-38° C. for 120 minutes with continuous stirring, this mixture is subjected to carbon treatment for 60 minute and the mixture is filtered through a hyflo bed and washed with dichloromethane; b. dichloromethane is distilled off from the reaction mixture at temperature not exceeding 40° C. to obtain a solid mixture having the dilauryl glyceryl fumarate of itraconazole; and c. dilauryl glyceryl fumarate of itraconazole is isolated from the solid mixture by washing, filtering drying the solid mixture in hexane to yield above 98.7% dilauryl glyceryl fumarate of itraconazole as a solid.

10. The triazole salts prepared by the process according to claim 7, are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron through.

11. The triazole salts prepared by the process according to claim 8, are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron through.

12. The triazole salts prepared by the process according to claim 9, are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron through.

13. The process according to claim 6, wherein the preparation of dilauryl glyceryl fumarate of posaconazole comprises of: a. dissolving posaconazole and dilaurylglyceryl fumarate in the acetonitrile and heating the reaction mixture to a temperature about 50-55° C. for 180 minutes with continuous stirring to obtain a clear solution; b. acetonitrile is distilled off from the reaction mixture at temperature not exceeding 40° C. to obtain a solid having the dilauryl glyceryl fumarate of posaconazole; and c. dilauryl glyceryl fumarate of posaconazole is isolated from the solid of step b by washing and filtering the solid in hexane to yield above 97.3% dilauryl glyceryl fumarate of posaconazole.

14. The process as claimed in claim 6, wherein the preparation of dilauryl glyceryl fumarate of voriconazole comprises of: a. dissolving voriconazole and dilaurylglyceryl fumarate in the acetonitrile and heating the reaction mixture to a temperature about 50-55° C. for 180 minutes with continuous stirring to obtain a clear solution; b. acetonitrile is distilled off from the reaction mixture at temperature not exceeding 40° C. to obtain a solid mixture having the dilauryl glyceryl fumarate of voriconazole; and c. dilauryl glyceryl fumarate of voriconazole is isolated from the solid mixture by washing, filtering drying the solid mixture in hexane to yield above 98.8% dilauryl glyceryl fumarate of voriconazole as a solid.

15. The process as claimed in claim 6, wherein the preparation of dilauryl glyceryl fumarate of itraconazole comprises of: a. dissolving itraconazole and dilaurylglyceryl fumarate in the dichloromethane and heating the reaction mixture to a temperature about 35-38° C. for 120 minutes with continuous stirring, this mixture is subjected to carbon treatment for 60 minute and the mixture is filtered through a hyflo bed and washed with dichloromethane; b. dichloromethane is distilled off from the reaction mixture at temperature not exceeding 40° C. to obtain a solid mixture having the dilauryl glyceryl fumarate of itraconazole; and c. dilauryl glyceryl fumarate of itraconazole is isolated from the solid mixture by washing, filtering drying the solid mixture in hexane to yield above 98.7% dilauryl glyceryl fumarate of itraconazole as a solid.

16. The triazole salts prepared by the process according to claim 13, are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron through.

17. The triazole salts prepared by the process according to claim 14, are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron through.

18. The triazole salts prepared by the process according to claim 15, are processed using a chemical process or physical manipulation to obtain a particle size ranging from 0.001 micron to 100 micron through.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention discloses the process for preparation of dilauryl glyceryl fumarate salt of posaconazole, voriconazole and itraconazole respectively. Salt formation was evaluated using various polar protic solvents (such as methanol, ethanol, isopropanol and water), aprotic solvents like acetonitrile, methyl tertiary butyl ether (MTBE) and chlorinated solvents (like dichloromethane, chloroform etc.) at different temperature (30-55° C.) for different time intervals. The solvent was removed under vacuum to yield the compound as solid. Isolation of final salt was performed using various cyclic and acyclic hydrocarbons (cyclohexane, hexane, heptane etc.) at temperature ranging from 0-35° C.

[0016] In an embodiment the triazole salt is processed to a fine material having particle size ranging from 0.001 micron to 100 microns through chemical process or physical manipulation (milling or micronisation).

[0017] Posaconazole Dilaurylglyceryl Fumarate

[0018] IUPAC name: [4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)-1-(4-(1-((2S,S5)-2-hydroxypentan-3-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl) piperazin-1-ium-(E)-4-((1,3-bis(dodecanoyloxy) propan-2-yl)oxy)-4-oxobut-2-enoate]

[0019] Reference code: (CLX-SYN-G159-009E).

Preparation of posaconazole dilauryl glyceryl fumarate

[0020] In an embodiment, the posaconazole and dilaurylglyceryl fumarate were suspended in acetonitrile and reaction mixture was heated to 50-55° C. to get a clear solution and temperature was maintained for 3 hr with continuous stirring. Solvent was distilled off at temperature not exceeding 40° C. under vacuum to get a solid. To this hexane was added at room temperature with stirring and then removed under vacuum. Again, hexane was added, and contents were cooled to 0-5° C. and stirred for 60 min, filtered, washed with hexane and dried at 30-45° C. to get white to off-white powder.

[0021] During salt formation, various polar solvents (like acetonitrile, isopropanol and water) were evaluated at temperature ranging from 50° C.- to 55° C. Use of acetonitrile has resulted in better yield (87-90%) as compared to other solvents. Hence, acetonitrile is found to be a suitable solvent for dissolution of posaconazole and dilaurylglyceryl fumarate for salt formation.

[0022] Use of various non-polar cyclic and acyclic hydrocarbons (cyclohexane, hexane and heptane) was evaluated for isolation of final compound at 0-5° C. Hexane is found to be the best solvent to yield better yield (97%) of the desired compound.

[0023] The detailed optimized process for the preparation of Posaconazole dilaurylglyceryl fumarate is described below:

Example 1

[0024] ##STR00001##

Step-I: Preparation of Posaconazole dilauryl glyceryl fumarate

[0025] To a solution of Posaconazole (320 g, 0.456 gmole) in acetonitrile (6.4 lt) was added (E)-4-((1,3-bis(didecanoyloxy)propane-2-yl)oxy)-4-oxobut-2-enoic acid (253 gm, 0.456 gmole) at room temperature (25-30° C.). The resulting mixture was heated to 50-55° C. and stirred for 180 minutes at 50-55° C. The contents were filtered, and solvent was removed at temperature not exceeding 40° C. under vacuum to yield a white solid.

Step-II: Crystallization of Posaconazole dilauryl glyceryl fumarate

[0026] The solid was taken in hexane (320 ml) under stirring and solvent was removed under vacuum at 40° C. To the residue, hexane (1.6 lt) was added and contents were cooled to 0-5° C. with continuous stirring and then filtered followed by washing with hexane (320 ml). The solid was dried at 35-40° C. under vacuum to yield the final compound as off white powder (558 g; 97.3% yield).

[0027] Chemical Formula: C.sub.68H.sub.96F.sub.2N.sub.8O.sub.12; Molecular Weight: 1255.56;

[0028] .sup.1H NMR (400 MHZ, DMSO-d.sub.6 solvent): .sup.1H NMR chemical shifts are reported on the δ scale in ppm relative to TMS (δ 0.00) as internal reference standard and NMR assignments are shown on the following page:

##STR00002##

[0029] NMR assignments of Posaconazole dilaurylglyceryl fumarate are shown below:

TABLE-US-00001 Position.sup.1 δ (ppm and Hz) Position.sup.1 δ (ppm and Hz) H5 7.77 (s, 1H) H20, H24, 3.32-3.14 (m, 8H) H21, H23 H7 1.12 (d, 3H) H26, H30 6.93 (d, 2H) H8 3.83 (m, 1H) H27, H29 6.79 (d, 2H) H9 3.80 (m, 1H) H32 4.02 (t, 1H); 3.66 (t, 1H) H10 1.70 (m, 2H) H34 3.69 (m, 1H); 3.63 (m, 1H) H11 0.74 (t, 3H) H35 2.53 (m, 1H) H12 4.66 (d, 1H) H36 2.13 (m, 1H); 2.39 (m, 1H) H14, H18 7.50 (d, 2H) H38 4.57 (m, 2H) H15, H17 7.11 (d, 2H) H41, H43 8.34-8.33 (d, 2H) H46 7.01 (m, 1H) H48, H49 7.30-7.25 (m, 2H) H52 13.27 (s, 1H) H54, H56 6.66 (m, 2H) H61 4.22 (m, 2H) H60 5.29 (m, 1H) H66, H80 2.28 (t, 4H) H62 4.31 (d, 2H) H76 & H90 0.84 (t, 6H) H67, H81 1.46 (m, 4H) H68, H69, H70, 1.26 (m, 32H) — — H71, H72, H73, H74, H75 H82, H83, H84, H85, H86, H87, H88, H89

[0030] Itraconazole Dilaurylglyceryl Fumarate

[0031] IPUAC name: 1-((4-((4-(4-(4-(1-(sec-butyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)piperazin-1-yl)phenoxy)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazol-1-ium-((E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate Ref code: (CLX-SYN-G159-007E)

Preparation of Itraconazole dilauryl glyceryl fumarate

[0032] In an embodiment itraconazole and dilaurylglyceryl fumarate were suspended in dichloromethane and mixture was heated to 35-38° C. to get a clear solution. Reaction temperature was maintained for 3 hr with continuous stirring. The solvent was distilled off to get a solid. To this hexane was added with stirring at 25-30° C. and removed under vacuum. This solid was taken in hexane and contents were stirred at 25-30° C. and cooled to 0-5° C., filtered and washed with hexane. The material was dried at 45-50° C. to get off-white to light yellow powder.

[0033] During salt formation, various polar solvents (like acetonitrile, tetrahydrofuran and chlorinated solvent (such as dichloromethane) were evaluated at temperature ranging from 35° C.- to 55° C. Use of acetonitrile did not result in a clear solution. Though a clear solution was obtained when salt formation was performed in tetrahydrofuran/dichloromethane. Dichloromethane has resulted in good yield (97%) as compared to THF (95%). Hence, dichloromethane is found to be a suitable solvent for dissolution of Iitraconazole and dilaurylglyceryl fumarate during for salt formation.

[0034] Effect of reaction duration during salt formation was evaluated by maintaining the reaction temperature for different time intervals (30 min to 5 hr). Maintaining the reaction temperature for 3 hr has resulted in better yield.

[0035] Use of various non-polar cyclic and acyclic hydrocarbons (cyclohexane, hexane and heptane) was evaluated for isolation of final compound. Hexane is found to be the best solvent to yield better yield (95%) of the desired compound.

[0036] Effect of temperature on isolation of compound using hexane as a solvent was studied at 0-15° C. and 25-30° C. Isolation of final compound at lower temperature (0-5° C.) has resulted in good yield (96%) as compared to higher temperature.

[0037] The detailed optimized process for the preparation of Itraconazole dilaurylglyceryl fumarate is described on the following page:

Example 2

[0038] ##STR00003##

Step-I: Preparation of Itraconazole dilauryl glyceryl fumarate

[0039] Itraconazole (270 gm, 0.382 gmole) was added to solution of (E)-4-((1,3-bis(didecanoyloxy)propanes-2-yl)oxy)-4-oxobut-2-enoic acid (212.22 g, 0.382 gmole) in dichloromethane (2.7 lt) at 25-30° C. The resulting solution was heated to reflux (35-38° C.) with continuous stirring for 120 min. This was given carbon treatment for 60 min and filtered through hyflo bed followed by washing with dichloromethane (1.35 lt). The solvent was removed under vacuum at temperature not exceeding 40° C.

Step-II: Crystallisation of Itraconazole dilaurylglyceryl fumarate

[0040] The solid was taken in hexane (1.08 lt) under stirring and solvent was removed under vacuum at 40° C. To the residue, hexane (3.78 lt) was added and contents were cooled to 0-5° C. with continuous stirring and then filtered followed by washing with hexane (1.08 lt). The solid was dried at 45-50° C. under vacuum to yield the final compound as light yellow solid (476 gm, yield 98.7%).

[0041] Chemical Formula: C.sub.66H.sub.92Cl.sub.2N.sub.8O.sub.12; Molecular Weight: 1260.41 .sup.1H NMR (400 MHZ, DMSO-d.sub.6 solvent): .sup.1H NMR chemical shifts are reported on the δ scale in ppm relative to TMS (δ 0.00) as internal reference standard and NMR assignments are shown on the following page:

##STR00004##

[0042] NMR assignments of Itraconazole dilaurylglyceryl fumarate are shown below:

TABLE-US-00002 Position.sup.1 δ (ppm and Hz) Position.sup.1 δ (ppm and Hz) H1 0.79 (t)-3H H32 7.67 (d)-1H H2 1.22 (m)-2H H33 7.41 (dd)-1H H3 3.92 (m)-1H H36 7.67 (d)-1H H8 & H45 7.10 (d)-2H H46 7.87 (s)-1H H9 & H44 6.97 (d)-2H H49 1.26 (m)-3H H12 & H43 3.19 (m)-4H H50 4.82 (m)-1H H13 & H42 3.33 (m)-4H H51 & H66 4.35 (m)-2H, 4.31 (m)-2H H16 & H41 6.85 (d)-2H H55 & H70 2.28 (m)-4H H17 & H40 6.67 (q)-2H H56 & H71 1.47 (m)-4H H20 3.92(m)-1H; H57, H58, H59, 1.22 (m)-32H 4.92(m)-1H H60, H61, H62, H63, H64, H72, H73, H74, H75, H76, H77, H78, H79 H21 4.81 (m)-1H H65 & H80 081 (m)-6H H22 3.75 (m)-2H H84 7.41 (d)-1H H25 4.24 (m)-2H H85 7.52 (d)-1H H27 8.44 (s)-1H H87 13.21 (s)-1H H29 8.41 (s)-1H — —

[0043] Voriaconazole Dilaurylglyceryl Fumarate

[0044] IUPAC NAME: [4-((2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-5-fluoropyrimidin-1-ium-(E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate] (CLX-SYN-G159-C10E):

Preparation of Voriconazole dilauryl glyceryl fumarate

[0045] In another embodiment the voriconazole and dilaurylglyceryl fumarate were suspended in an acetonitrile and contents were heated to 50-55° C. to get a clear solution and stirring was continued for 3 hr. Solvent was distilled off to get a solid. To this hexane was added with stirring at 25-30° C. and removed under vacuum. This solid was taken in hexane and contents were stirred at 25-30° C. and cooled to 0-5° C., filtered and washed with hexane. The material was dried at 35-40° C. to get white to off-white solid.

[0046] During preparation of salt formation, various polar protic solvents (like Methanol, Ethanol, Isopropanol and Water) and aprotic solvents (acetonitrile, chlorinated solvent (dichloromethane, chloroform) were used at temperature ranging from 40° C.- to 55° C. Use of acetonitrile has resulted in good yield.

[0047] Use of various polar (Acetonitrile, Methanol, Isopropanol, Methyl tertiary butyl ether (MTBE) and Water) and non-polar solvents [cyclic and acyclic hydrocarbons (cyclohexane, hexane and heptane)] was studied. Hexane is found to be the best solvent to yield better yield (95%) of the desired compound.

[0048] Effect of temperature on isolation of compound using hexane as a solvent was studied at 0-15° C. and isolation at lower temperature (0-5° C.) has resulted in good yield (96%) as compared to higher temperature.

[0049] The detailed optimized process for the preparation of Voriconazole dilaurylglyceryl fumarate is described below:

Example 3

[0050] ##STR00005##

Step-I: Preparation of Voriconazole dilauryl glyceryl fumarate

[0051] Voriconazole (230 gm, 0.658 gmole) was added to a solution of (E)-4-((1,3-bis(didecanoyloxy)propane-2-yl)oxy)-4-oxo but-2-enoic acid (365.5 gm, 0.658 gmole) in acetonitrile (6.9 lt) at room temperature (25-35° C.). The resulting mixture was heated to 50-55° C. and stirred for 180 minutes at 50-55° C. The mixture was filtered, and solvent was removed under vacuum at temperature not exceeding 40° C.

Step-II: Crystallization of Voriconazole dilauryl glyceryl fumarate

[0052] The solid was taken in hexane (460 ml) under stirring at 25-30° C. and solvent was removed under vacuum at 40° C. To the residue, hexane (1.1510 was added under stirring and contents were cooled to 0-5° C., stirred for 60 min and then filtered. The solid was washed with hexane (230 ml) and material was dried at 35-40° C. under vacuum to yield the final compound as off white powder (588 g; 98.8% yield).

[0053] Chemical Formula: C.sub.47H.sub.68F.sub.3N.sub.5O.sub.9; Molecular Weight: 904.09

[0054] .sup.1H NMR (400 MHZ, DMSO-d.sub.6 solvent): 1H NMR chemical shifts are reported on the δ scale in ppm relative to TMS (δ 0.00) as internal reference standard and NMR assignments are shown as below.

##STR00006##

[0055] NMR assignments of Voriconazole dilaurylglyceryl fumarate are shown below:

TABLE-US-00003 Position.sup.1 δ (ppm and Hz) Position δ (ppm and Hz) H2 4.22 (d, 2H) H10, H11, H12, H13, 1.26 (m, 32H) H14, H15, H16, H17, H23, H24, H25, H26, H27, H28, H29, H30 H3 5.29 (m, 1H) H18 & H31 0.84 (t, 6H) H4 4.31 (m, 2H) H34, H35 6.66 (m, 2H) H8, H21 2.28 (t, 4H) H38 13.27 (s, 1H) H9, H22 1.46 (m, 4H) H41 3.95 (q, 1H) H40 1.13 (d, 3H) H47 9.06 (d, 2H) H45 8.87 (d, 1H) H50 7.17 (m, 1H) H49 7.27 (m, 1H) H57 5.99 (s, 1H) H53 6.92 (m, 1H) H61 8.24 (s, 1H) H59 4.37 (d, 1H); H63 7.62 (s, 1H) 4.83 (d, 1H)