WO2008035360A2 - Novel crystalline forms of candesartan cilexetil, candesartan, tritylated candesartan and tritylated candesartan cilexetil - Google Patents
Novel crystalline forms of candesartan cilexetil, candesartan, tritylated candesartan and tritylated candesartan cilexetil Download PDFInfo
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- WO2008035360A2 WO2008035360A2 PCT/IN2007/000236 IN2007000236W WO2008035360A2 WO 2008035360 A2 WO2008035360 A2 WO 2008035360A2 IN 2007000236 W IN2007000236 W IN 2007000236W WO 2008035360 A2 WO2008035360 A2 WO 2008035360A2
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- WIPO (PCT)
- Prior art keywords
- candesartan
- methyl
- novel crystalline
- tritylated
- candesartan cilexetil
- Prior art date
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- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 47
- 239000002053 C09CA06 - Candesartan Substances 0.000 title claims abstract description 36
- 229960000932 candesartan Drugs 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 40
- HTQMVQVXFRQIKW-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 HTQMVQVXFRQIKW-UHFFFAOYSA-N 0.000 claims description 37
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 25
- 238000001228 spectrum Methods 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- -1 2'-cyanobiphenyl-4-yl Chemical group 0.000 claims description 10
- VVQNAFBGAWCMLU-UHFFFAOYSA-N 1h-benzimidazole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1N=CN2 VVQNAFBGAWCMLU-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 4
- ONZWFHWHTYZZLM-UHFFFAOYSA-N 1-chloroethyl cyclohexyl carbonate Chemical compound CC(Cl)OC(=O)OC1CCCCC1 ONZWFHWHTYZZLM-UHFFFAOYSA-N 0.000 claims description 3
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 claims description 3
- 229940078552 o-xylene Drugs 0.000 claims description 3
- BCDGQXUMWHRQCB-UHFFFAOYSA-N glycine methyl ketone Natural products CC(=O)CN BCDGQXUMWHRQCB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- VBMKOTRJWPIKMG-UHFFFAOYSA-N 2-ethoxy-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VBMKOTRJWPIKMG-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- KSXLHOFDCDKQLH-UHFFFAOYSA-N methyl 3-[[4-(2-cyanophenyl)phenyl]methyl]-2-ethoxybenzimidazole-4-carboxylate Chemical compound CCOC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C#N KSXLHOFDCDKQLH-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940058087 atacand Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229950006523 cilexetil Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- WRBLBPRJIBIRBP-UHFFFAOYSA-N cyclohexyl 1-iodoethyl carbonate Chemical compound CC(I)OC(=O)OC1CCCCC1 WRBLBPRJIBIRBP-UHFFFAOYSA-N 0.000 description 1
- VTDCYOLLYVAJSY-UHFFFAOYSA-N cyclohexyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OC1CCCCC1 VTDCYOLLYVAJSY-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- the present invention relates to novel crystalline forms of Candesartan cilexetil and intermediate thereof. Particularly, the present invention relates to two novel crystalline forms of candesartan cilexetil which are designated as form G and form H and a novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil and process for their preparation.
- Candesartan cilexetil is 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1 -[[2-(IH-tetazole-5-yl)[1 , 1 '-biphenyl-4-yl]methyl]-IH-benzimidazole-7- carboxylate. Its molecular formula is 0 33 Ha 4 NeO 6 and mol wt is 610.66. Candesartan cilexetil is represented by structural formula (I).
- Candesartan cilexteil is an ester prodrug of 2-ethoxy-1-[[2-(IH-tetrazole-5-yl)[1 ,1'- biphenyl-4-yl]methyl]-1 H benzimidazole-7-carboxylic acid (candesartan), known as a potent Angiotensin Il receptor antagonist. It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure.
- Candesartan cilexetil is a white to off-white powder and is sparingly soluble in water and in methanol. It is marketed by AstraZeneca under tradename ATACAND ® .
- 5,196,444 relates to crystal form of Candesartan Cilexetil i.e. C-type crystal (form I) and it describes a process of preparation of Candesartan cilexetil in which it is formed by reacting 2-ethoxy-1-[[2'-(N-triphenyImethyltetrazol-5-yl)biphenyl -4-yl]methyl]benzimidazole-7-carboxylic acid in dimethylformamide with cyclohexyl- 1-iodoethyl carbonate to form cilexetil trityl candesartan and its subsequent deprotection with a methanolic hydrochloric acid gives candesartan cilexetil in 47% yield after column chromatography.
- the yield of C-type crystal obtained by this process is very low.
- the purification of final product by chromatography is commercially not suitable and is cumbersome at an industrial scale.
- Candesartan cilexetil such as form I and form Il and an amorphous form.
- candesartan cilexetil is heat sensitive and therefore grinding causes unwanted degradation and loss in purity.
- WO2004085426 discloses 1 , 4-dioxane solvate and two crystalline forms of candesartan cilexetil.
- WO2005077941 describes a process for the preparation of polymorphic forms of Candesartan cilexetil i.e. form-Ill, form-IV, form-V, form-VI, form-VII, form-VIII, form- IX, form-X, form-XI, form-XIII, form-XIV, form-XIV-1 , form-XV, form-XVI, form-XVII, form-VIII, form-XIX, form-XX, form-XXI, form-XXII or XXIII, having less than about 5% by weight of other polymorphic forms (form-l).
- These forms are hydrates and solvates of candesartan cilexetil.
- WO2005123721 A1 describes a process for the preparation of two crystalline forms i.e. form A, form B and an amorphous form. The process disclosed hereinabove are tedious, time consuming and operationally difficult at industrial scale.
- WO2006048237 A1 describes a process for the preparation of form 5, form 6, form 7, form 8 and amorphous form. These forms are prepared by dissolving candesartan cilexetil in a chlorinated solvent, optionally concentrate thus obtain solution then liquid hydrocarbon is added to the solution to precipitate out these forms.
- a primary object of the present invention is to provide novel crystalline forms of Candesartan cilexetil i.e. form G and form H.
- Another object of the present invention is to provide a process for the preparation novel crystalline forms of Candesartan cilexetil i.e. form G and form H, which is simple and easy to handle at an industrial scale and cost effective.
- Another object of the present invention is to provide a process for the preparing candesartan form G comprising steps of i) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution ii) cooling the said solution at O 0 C to 5 0 C
- Yet another object of the present invention is to provide a process for the preparing candesartan form H comprising a step of heating candesartan cilexetil form G at 75°C under reduced pressure.
- a further object of the present invention is to provide novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
- An aspect of the present invention is to provide novel crystalline forms of Candesartan cilexetil i.e. form G and form H.
- Another aspect of the present invention is to provide a process for the preparing candesartan form G comprising steps of iii) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution iv) cooling the said solution at 0 0 C to 5°C
- Yet another aspect of the present invention is to provide a process for the preparing candesartan form H comprising a step of heating candesartan cilexetil form G at 75°C under reduced pressure.
- a further aspect of the present invention is to provide novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
- Figure-1 is an X-ray powder diffraction pattern of candesartan cilexetil form
- Figure-2 is an X-ray powder diffraction pattern of candesartan cilexetil form
- Figure-3 is an X-ray powder diffraction pattern of novel crystalline form of candesartan
- Figure-4 is an X-ray powder diffraction pattern of novel crystalline form of tritylated candesartan
- Figure-5 is an X-ray powder diffraction pattern of novel crystalline form of tritylated candesartan cilexetil
- a novel crystalline form of Candesartan cilexetil designated as form G, characterized by an X-ray powder diffraction spectrum having peaks at about 6.1 , 7.2, 9.1 , 10.9, 11.9, 12.6, 13.1 , 16.4, 20.0, 20.8 and 23.3 ⁇ 0.2 degree two-theta.
- Figure-1 depicts the X-ray powder diffraction spectrum of candesartan cilexetil form G.
- a process for preparation of the form G of candesartan cilexetil comprising steps of i) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution ii) cooling the said solution at 0 0 C to 5°C
- a novel crystalline form of Candesartan cilexetil designated as form H, characterized by an X-ray powder diffraction spectrum having peaks at about 9.2, 12.0, 13.0, 15.3, 16.1, 16.7, 17.2, 20.7, 21.0, 25.7 and 32.8 ⁇ 0.2 degree two-theta.
- Figure-2 depicts the X-ray powder diffraction spectrum of candesartan cilexetil form H.
- a process for preparation of the form H of candesartan cilexetil comprising a step of heating candesartan cilexetil form G at 75 0 C under reduced pressure.
- the present invention is to provide a novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
- FIG. 1 One aspect of the present invention, there is provided a novel crystalline form of candesartan, characterized by an X-ray powder diffraction spectrum having peaks at about 10.4, 11.6, 13.8, 19.1 , 20.6, 20.8, 21.8, 22.6, 23.3, 26.1 , 28.3 and 30.3 ⁇ 0.2 degree two-theta.
- Figure-3 depicts the X-ray powder diffraction spectrum of a novel crystalline form of candesartan.
- a novel crystalline form of candesartan is prepared by reacting methyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2- ethoxy-benzimidazole-7-carboxylate with sodium azide, tri butyl tin chloride in the presence of o-xylene at 135-15O 0 C to obtain methyl 2-ethoxy- 1-[(2'- ⁇ 1H-tetrazole-5- yl ⁇ biphenyl-4-yl)-methyl] benzimidazole-7-carboxylate which is hydrolyzed in the presence of sodium hydroxide at 80-85 0 C and recrystallized in acetone to obtain novel crystalline form of Candesartan (2-ethoxy- 1-[(2'- ⁇ 1 H-tetrazole-5-yl ⁇ biphenyl-4- yl)-methyl] benzimidazole-7-carboxylic acid).
- a novel crystalline form of tritylated candesartan characterized by an X-ray powder diffraction spectrum having peaks at about 8.7, 9.4, 9.7, 11.6, 14.0, 14.4, 14.9, 18.2, 20.8, 21.1, 21.7, 23.1 , 25.4, 26.5 and 27.0 ⁇ 0.2 degree two-theta.
- Figure-4 depicts the X-ray powder diffraction spectrum of novel crystalline form of tritylated candesartan.
- a novel crystalline form of tritylated candesartan is prepared by reacting 2-ethoxy- 1 ⁇ [(2'- ⁇ 1 H-tetrazole-5-yl ⁇ biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid with trityl chloride solution in the presence of acetone and triethylamine to obtain novel crystalline form of tritylated candesartan (2-ethoxy- 1-[(2'- ⁇ N-tri phenyl methyl tetrazole-5-yl ⁇ biphenyl- 4-yl)-methyl] benzimidazole-7-carboxylic acid ).
- a novel crystalline form of tritylated candesartan cilexetil characterized by an X-ray powder diffraction spectrum having peaks at about 8.6, 9.0, 9.7, 10.3, 12.0, 12.8, 15.2, 15.8, 16.2, 16.5, 17.3, 19.5, 19.8, 21.0, 21.4, 22.1 , 22.4 and 26.1 ⁇ 0.2 degree two-theta.
- Figure- 5 depicts the X-ray powder diffraction spectrum of novel crystalline form of tritylated candesartan cilexetil.
- a novel crystalline form of tritylated candesartan cilexetil is prepared by reacting 2-ethoxy- 1-[(2'- ⁇ N-tri phenyl methyl tetrazole-5-yl ⁇ biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid with cyclohexyl 1-chloroethylcarbonate in the presence of dimethylformamide, potassium ' carbonate to obtain tritylated candesartan cilexetil which is recrystallized in acetone to obtain novel crystalline form of tritylated candesartan cilexetil (( ⁇ )-1- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy- 1-[(2'- ⁇ N-tri phenyl methyl tetrazole-5- yl ⁇ biphenyl-4-yl)-methyl] benzimidazole
- a solution of sodium azide (71.15 g) in D. M. water (214 ml) was prepared in round bottom flask and cooled to 0-10° C.
- Tri-n-butyl tin chloride (237.58 g) was added to the reaction mass at 0-10° C within 30-60 minutes. Reaction mixture was stirred for 2 hours at 0-10° C.
- O-xylene (1000 ml) was added to it and stirred. The o-xylene layer was separated and washed with 20 % brine solution.
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Abstract
The present invention provides two novel crystalline forms of candesartan cilexetil which are designated as form G and form H and a novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil and process for their preparation thereof.
Description
NOVEL CRYSTALLINE FORMS
Field of invention:
The present invention relates to novel crystalline forms of Candesartan cilexetil and intermediate thereof. Particularly, the present invention relates to two novel crystalline forms of candesartan cilexetil which are designated as form G and form H and a novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil and process for their preparation.
Background of the invention:
The chemical name of Candesartan cilexetil is 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1 -[[2-(IH-tetazole-5-yl)[1 , 1 '-biphenyl-4-yl]methyl]-IH-benzimidazole-7- carboxylate. Its molecular formula is 033Ha4NeO6 and mol wt is 610.66. Candesartan cilexetil is represented by structural formula (I).
Candesartan cilexteil is an ester prodrug of 2-ethoxy-1-[[2-(IH-tetrazole-5-yl)[1 ,1'- biphenyl-4-yl]methyl]-1 H benzimidazole-7-carboxylic acid (candesartan), known as a potent Angiotensin Il receptor antagonist. It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure. Candesartan cilexetil is a white to off-white powder and is sparingly soluble in water and in methanol. It is marketed by AstraZeneca under tradename ATACAND®.
U.S. Pat. No. 5,196,444 relates to crystal form of Candesartan Cilexetil i.e. C-type crystal (form I) and it describes a process of preparation of Candesartan cilexetil in which it is formed by reacting 2-ethoxy-1-[[2'-(N-triphenyImethyltetrazol-5-yl)biphenyl -4-yl]methyl]benzimidazole-7-carboxylic acid in dimethylformamide with cyclohexyl- 1-iodoethyl carbonate to form cilexetil trityl candesartan and its subsequent deprotection with a methanolic hydrochloric acid gives candesartan cilexetil in 47% yield after column chromatography. The yield of C-type crystal obtained by this process is very low. Moreover, the purification of final product by chromatography is commercially not suitable and is cumbersome at an industrial scale.
Chem. Pharm. Bull., 47(2), 182-186 (1999) discloses two crystalline forms of
Candesartan cilexetil such as form I and form Il and an amorphous form. In addition, candesartan cilexetil is heat sensitive and therefore grinding causes unwanted degradation and loss in purity.
WO2004085426 discloses 1 , 4-dioxane solvate and two crystalline forms of candesartan cilexetil.
WO2005077941 describes a process for the preparation of polymorphic forms of Candesartan cilexetil i.e. form-Ill, form-IV, form-V, form-VI, form-VII, form-VIII, form- IX, form-X, form-XI, form-XIII, form-XIV, form-XIV-1 , form-XV, form-XVI, form-XVII, form-VIII, form-XIX, form-XX, form-XXI, form-XXII or XXIII, having less than about 5% by weight of other polymorphic forms (form-l). These forms are hydrates and solvates of candesartan cilexetil.
WO2005123721 A1 describes a process for the preparation of two crystalline forms i.e. form A, form B and an amorphous form. The process disclosed hereinabove are tedious, time consuming and operationally difficult at industrial scale.
WO2006048237 A1 describes a process for the preparation of form 5, form 6, form 7, form 8 and amorphous form. These forms are prepared by dissolving candesartan cilexetil in a chlorinated solvent, optionally concentrate thus obtain solution then liquid hydrocarbon is added to the solution to precipitate out these forms.
Objects of the invention:
A primary object of the present invention is to provide novel crystalline forms of Candesartan cilexetil i.e. form G and form H.
Another object of the present invention is to provide a process for the preparation novel crystalline forms of Candesartan cilexetil i.e. form G and form H, which is simple and easy to handle at an industrial scale and cost effective.
Another object of the present invention is to provide a process for the preparing candesartan form G comprising steps of i) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution ii) cooling the said solution at O0C to 50C
Yet another object of the present invention is to provide a process for the preparing candesartan form H comprising a step of heating candesartan cilexetil form G at 75°C under reduced pressure.
A further object of the present invention is to provide novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
Summary of the invention
An aspect of the present invention is to provide novel crystalline forms of Candesartan cilexetil i.e. form G and form H.
Another aspect of the present invention is to provide a process for the preparing candesartan form G comprising steps of iii) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution iv) cooling the said solution at 00C to 5°C
Yet another aspect of the present invention is to provide a process for the preparing candesartan form H comprising a step of heating candesartan cilexetil form G at 75°C under reduced pressure.
A further aspect of the present invention is to provide novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
Brief description of the drawings Figure-1 is an X-ray powder diffraction pattern of candesartan cilexetil form G Figure-2 is an X-ray powder diffraction pattern of candesartan cilexetil form H Figure-3 is an X-ray powder diffraction pattern of novel crystalline form of candesartan Figure-4 is an X-ray powder diffraction pattern of novel crystalline form of tritylated candesartan
Figure-5 is an X-ray powder diffraction pattern of novel crystalline form of tritylated candesartan cilexetil
Detailed description of the invention:
According to the present invention, it provides novel crystalline forms of
Candesartan cilexetil i.e. form G and form H.
One aspect of the present invention, there is provided a novel crystalline form of Candesartan cilexetil, designated as form G, characterized by an X-ray powder
diffraction spectrum having peaks at about 6.1 , 7.2, 9.1 , 10.9, 11.9, 12.6, 13.1 , 16.4, 20.0, 20.8 and 23.3 ±0.2 degree two-theta. Figure-1 depicts the X-ray powder diffraction spectrum of candesartan cilexetil form G.
According to another aspect of the present invention, there is provided a process for preparation of the form G of candesartan cilexetil comprising steps of i) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution ii) cooling the said solution at 00C to 5°C
One aspect of the present invention, there is provided a novel crystalline form of Candesartan cilexetil, designated as form H, characterized by an X-ray powder diffraction spectrum having peaks at about 9.2, 12.0, 13.0, 15.3, 16.1, 16.7, 17.2, 20.7, 21.0, 25.7 and 32.8 ±0.2 degree two-theta. Figure-2 depicts the X-ray powder diffraction spectrum of candesartan cilexetil form H.
According to another aspect of the present invention, there is provided a process for preparation of the form H of candesartan cilexetil comprising a step of heating candesartan cilexetil form G at 750C under reduced pressure.
Yet another embodiment, the present invention is to provide a novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
One aspect of the present invention, there is provided a novel crystalline form of candesartan, characterized by an X-ray powder diffraction spectrum having peaks at about 10.4, 11.6, 13.8, 19.1 , 20.6, 20.8, 21.8, 22.6, 23.3, 26.1 , 28.3 and 30.3 ±0.2 degree two-theta. Figure-3 depicts the X-ray powder diffraction spectrum of a novel crystalline form of candesartan.
According to another aspect of the present invention, a novel crystalline form of candesartan is prepared by reacting methyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2- ethoxy-benzimidazole-7-carboxylate with sodium azide, tri butyl tin chloride in the presence of o-xylene at 135-15O0C to obtain methyl 2-ethoxy- 1-[(2'-{1H-tetrazole-5- yl} biphenyl-4-yl)-methyl] benzimidazole-7-carboxylate which is hydrolyzed in the presence of sodium hydroxide at 80-850C and recrystallized in acetone to obtain novel crystalline form of Candesartan (2-ethoxy- 1-[(2'-{1 H-tetrazole-5-yl} biphenyl-4- yl)-methyl] benzimidazole-7-carboxylic acid).
One aspect of the present invention, there is provided a novel crystalline form of tritylated candesartan, characterized by an X-ray powder diffraction spectrum having peaks at about 8.7, 9.4, 9.7, 11.6, 14.0, 14.4, 14.9, 18.2, 20.8, 21.1, 21.7, 23.1 , 25.4, 26.5 and 27.0 ±0.2 degree two-theta. Figure-4 depicts the X-ray powder diffraction spectrum of novel crystalline form of tritylated candesartan.
According to another aspect of the present invention, a novel crystalline form of tritylated candesartan is prepared by reacting 2-ethoxy- 1 ~[(2'-{1 H-tetrazole-5-yl} biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid with trityl chloride solution in the presence of acetone and triethylamine to obtain novel crystalline form of tritylated candesartan (2-ethoxy- 1-[(2'-{N-tri phenyl methyl tetrazole-5-yl} biphenyl- 4-yl)-methyl] benzimidazole-7-carboxylic acid ).
One aspect of the present invention, there is provided a novel crystalline form of tritylated candesartan cilexetil, characterized by an X-ray powder diffraction spectrum having peaks at about 8.6, 9.0, 9.7, 10.3, 12.0, 12.8, 15.2, 15.8, 16.2, 16.5, 17.3, 19.5, 19.8, 21.0, 21.4, 22.1 , 22.4 and 26.1 ±0.2 degree two-theta. Figure- 5 depicts the X-ray powder diffraction spectrum of novel crystalline form of tritylated candesartan cilexetil.
According to another aspect of the present invention, a novel crystalline form of tritylated candesartan cilexetil is prepared by reacting 2-ethoxy- 1-[(2'-{N-tri phenyl methyl tetrazole-5-yl}biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid with cyclohexyl 1-chloroethylcarbonate in the presence of dimethylformamide, potassium ' carbonate to obtain tritylated candesartan cilexetil which is recrystallized in acetone to obtain novel crystalline form of tritylated candesartan cilexetil ((±)-1- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy- 1-[(2'-{N-tri phenyl methyl tetrazole-5- yl}biphenyl-4-yl)-methyl] benzimidazole-7-carboxylate ).
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the ' invention in any manner.
Example-1
Preparation of Form G of candesartan cilexetil
10 g form C type solid (form-l) or mix form of candesartan cilexetil was dissolved in acetone (60 ml) and heated it to get clear solution at reflux temperature 50-55° C. The clear solution was cooled to 25-35° C and then further chilled it to 0-5° C and stirred for 2 hours. The solution was filtered and washed with chilled acetone (10 ml) and suck dried to obtain form G. X-ray powder diffraction pattern is matching with Figure-1.
Example-2
Preparation of Form H of candesartan cilexetil Form G was dried at 73-75° C under reduced pressure for about 48-50 hours to obtain form H (7.5 g) X-ray powder diffraction pattern is matching with Figure-2.
Example-3
Preparation of 2-Ethoxy- 1-[(2'-{1H-tetrazole-5-yl} biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid (CANDESARTAN)
A solution of sodium azide (71.15 g) in D. M. water (214 ml) was prepared in round bottom flask and cooled to 0-10° C. Tri-n-butyl tin chloride (237.58 g) was added to the reaction mass at 0-10° C within 30-60 minutes. Reaction mixture was stirred for 2 hours at 0-10° C. O-xylene (1000 ml) was added to it and stirred. The o-xylene layer was separated and washed with 20 % brine solution. Methyl 1-[(2'- cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylate (100 g) and o- xylene layer were taken into a round bottom flask and the temperature of reaction mixture was raised to 140-1450C & maintained for 8 hours. The reaction mass was cooled at 25-30° C and 5 % caustic solution was added to it. The reaction mass was heated to 80-85° C for 2 hours under stirring. After cooling the reaction mass, aqueous layer was separated. Acetone (700 ml) and sodium nitrite solution (41.95 gm sodium nitrite dissolved in 100 ml D. M. water) were added to aqueous layer and cooled to 0-15° C. The pH 3.7-4.3 was adjusted by dilute hydrochloric acid to obtain the desired compound. The product was filtered and washed with chilled D. M. water until neutral pH. Acetone (500 ml) was added to the wet cake and stirred for 1 hour at 25-35° C. The product was filtered, washed with acetone and dried at 25-35° C to obtain 90.0 g of title compound.
X-ray powder diffraction pattern is matching with Figure-3.
Example-4
Preparation of 2-Ethoxy- 1-[(2'-{N-tri phenyl methyl tetrazole-5-yl} biphenyl-4- yl)-methyl] benzimidazole-7-carboxylic acid (TRITYLATED CANDESARTAN)
2-ethoxy- 1-[(2'-{1H-tetrazole-5-yl} biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid (100 g), acetone (200 ml), triethylamine (27.55 g) were taken into round bottom flask and stirred. The reaction mass was refluxed at 55-6O0C and trityl chloride
solution (69.7 g trityl chloride dissolved in 400 ml acetone) was added within 1-2 hours and refluxed reaction mass for 7 hours at 55-600C. The reaction was cooled to 25-300C and stirred for 30 minutes. The product was filtered and washed with acetone (100 ml) and dried. D. M. water (500 ml) was added to wet cake and stirred it for 30 minutes. The product was filtered, washed with D. M. water (200 ml) and dried at 50-550C to obtain 117 g of title compound. X-ray powder diffraction pattern is matching with Figure-4.
Example-5 Preparation of (±)-i-(cyclohexyloxycarbonyloxy) ethyl-2-ethoxy- 1-[(2'-{N-tri phenyl methyl tetrazole-5-yl} biphenyl-4-yl)-methyl] benzimidazole-7- carboxylate (TRITYLATED CANDESARTAN CILEXETIL)
2-ethoxy- 1-[(2'-{N-tri phenyl methyl tetrazole-5-yl} biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid (100 g), dimethylformamide (200 ml), potassium carbonate (24.28 g) were taken into round bottom flask and stirred. The temperature of reaction mixture was raised to 60 to 7O0C and cyclohexyl 1-chloro ethyl carbonate
(36.33 g) was added within 1-2 hours and maintained at this temperature for 3 hours. The reaction mixture was cooled to 25 to 3O0C. The reaction mass was poured in D. M. water (800 ml) at 0 to 100C and stirred for 30 minutes at this temperature. The product was filtered and washed with chilled D. M. water until neutral pH. Acetone (500 ml) was added to wet cake and raised the temperature of reaction mixture to 55 to 6O0C. The reaction mixture was stirred for 30 minutes at 55 to 6O0C. The reaction mixture was cooled to 25 to 3O0C and stirred for 30 minutes at 25 to 3O0C. The product was filtered, washed with acetone (100 ml) and dried at 25 to 300C to obtain 115 g of title compound.
X-ray powder diffraction pattern is matching with Figure-5.
Claims
1. A novel crystalline form of Candesartan cilexetil, designated as form G, characterized by an X-ray powder diffraction spectrum having peaks at about 6.1 , 7.2, 9.1, 10.9, 11.9, 12.6, 13.1, 16.4, 20.0, 20.8 and 23.3 ±0.2 degree two-theta.
2. The process for the preparation of the form G of candesartan cilexetil comprising steps of, i) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution ii) cooling the said solution at 00C to 5°C
3. A novel crystalline form of Candesartan cilexetil, designated as form H, characterized by an X-ray powder diffraction spectrum having peaks at about
9.2, 12.0, 13.0, 15.3, 16.1, 16.7, 17.2, 20.7, 21.0, 25.7 and 32.8 ±0.2 degree two-theta.
4. The process for preparation of the form H of candesartan cilexetil comprising a step of heating candesartan cilexetil form G at 75°C under reduced pressure.
5. A novel crystalline form of candesartan, characterized by an X-ray powder diffraction spectrum having peaks at about 10.4, 11.6, 13.8, 19.1, 20.6, 20.8, 21.8, 22.6, 23.3, 26.1, 28.3 and 30.3 ±0.2 degree two-theta.
6. The process for the preparation of a novel crystalline form of candesartan comprising steps of,
« i) reacting methyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2~ethoxy- benzimidazole-7-carboxylate with sodium azide, tri butyl tin chloride in the presence of o-xylene at 135-15O0C to obtain methyl 2-ethoxy- 1-[(2'-{1 H-tetrazole-5-yl} biphenyl-4-yl)-methyl] benzimidazole-7- carboxylate; ii) hydrolyzing methyl 2-ethoxy- 1-[(2'-{1 H-tetrazole-5-yl} biphenyl-4- yl)-methyl] benzimidazole-7-carboxylate in the presence of sodium 5 hydroxide at 80-850C; and iii) recrystallizing the step (ii) in acetone to obtain novel crystalline form of candesartan (2-ethoxy- 1-[(2'-{1 H-tetrazole-5-yl} biphenyl-4-yl)- methyl] benzimidazole-7-carboxylic acid) 0 7. A novel crystalline form of tritylated candesartan, characterized by an X-ray powder diffraction spectrum having peaks at about 8.7, 9.4, 9.
7, 11.6, 14.0, 14.4, 14.9, 18.2, 20.
8, 21.1 , 21.7, 23.1, 25.4, 26.5 and 27.0 ±0.2 degree two- theta.
C 8. The process for the preparation of a novel crystalline form of tritylated candesartan comprising a step of, reacting 2-ethoxy- 1-[(2'-{1 H-tetrazole-5-yl} biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid with trityl chloride solution in the presence of acetone and triethylamine to obtain novel crystalline form of tritylated candesartan (2-ethoxy- 1-[(2'-{N-tri phenyl methyl0 tetrazole-5-yl} biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid).
9. A novel crystalline form of tritylated candesartan cilexetil, characterized by an X-ray powder diffraction spectrum having peaks at about 8.6, 9.0, 9.7, 10.3, 12.0, 12.8, 15.2, 15.8, 16.2, 16.5, 17.3, 19.5, 19.8, 21.0, 21.4, 22.1 , 22.4 and5 26.1 ±0.2 degree two-theta.
10. The process for the preparation of a novel crystalline form of tritylated candesartan cilexetil comprising steps of, i) reacting 2-ethoxy- 1-[(2'-{N-tri phenyl methyl tetrazole-5-0 yl}biphenyl-4-yl)~methyl] benzimidazole-7-carboxylic acid with cyclohexyl 1-chloroethylcarbonate in the presence of dimethylformamide, potassium carbonate to obtain tritylated candesartan cilexetil recrystallizing the step (ii) in acetone to obtain novel crystalline form of tritylated candesartan cilexetil ((±)-i-(cyclohexyloxycarbonyloxy) ethyl-2-ethoxy- 1-[(2'-{N-tri phenyl methyl tetrazole-5-yl}biphenyl-4- yl)-methyl] benzimidazole-7-carboxylate ).
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7692023B2 (en) | 2004-02-11 | 2010-04-06 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
| WO2010060564A1 (en) | 2008-11-27 | 2010-06-03 | Bayer Schering Pharma Aktiengesellschaft | Pharmaceutical dosage form comprising nifedipine or nisoldipine and an angiotensin-ii antagonist and/or a diuretic |
| WO2010146409A2 (en) | 2009-06-19 | 2010-12-23 | Nangenex, Inc. | Nanoparticulate candesartan cilexetil compositions, process for the preparation thereof and pharmaceutical compositions containing them |
| WO2011092666A1 (en) | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | An improved process for the preparation of candesartan cilexetil, polymorphic forms of n-trityl candesartan and their uses thereof |
| CN107709313A (en) * | 2015-06-05 | 2018-02-16 | 浙江华海药业股份有限公司 | A kind of method for preparing trityl candesartan |
| CN109627234A (en) * | 2019-01-30 | 2019-04-16 | 浙江省食品药品检验研究院 | A kind of candesartan cilexetil crystal and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| WO2004085426A1 (en) * | 2003-03-27 | 2004-10-07 | Hetero Drugs Limited | Novel crystalline forms of candesartan cilexetil |
| WO2005077941A2 (en) * | 2004-02-11 | 2005-08-25 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
| WO2005123721A2 (en) * | 2004-06-18 | 2005-12-29 | Ranbaxy Laboratories Limited | Amorphous and polymorphic forms of candesartan cilexetil |
| EP1655298A1 (en) * | 2004-11-03 | 2006-05-10 | LEK Pharmaceuticals d.d. | Novel polymorph forms of candesartan cilexetil |
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2007
- 2007-06-12 WO PCT/IN2007/000236 patent/WO2008035360A2/en active Application Filing
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7692023B2 (en) | 2004-02-11 | 2010-04-06 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
| WO2010060564A1 (en) | 2008-11-27 | 2010-06-03 | Bayer Schering Pharma Aktiengesellschaft | Pharmaceutical dosage form comprising nifedipine or nisoldipine and an angiotensin-ii antagonist and/or a diuretic |
| US9993432B2 (en) | 2008-11-27 | 2018-06-12 | Bayer Intellectual Property Gmbh | Pharmaceutical dosage form comprising nifedipine or nisoldipine and an angiotensin II antagonist and/or a diuretic |
| WO2010146409A2 (en) | 2009-06-19 | 2010-12-23 | Nangenex, Inc. | Nanoparticulate candesartan cilexetil compositions, process for the preparation thereof and pharmaceutical compositions containing them |
| WO2011092666A1 (en) | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | An improved process for the preparation of candesartan cilexetil, polymorphic forms of n-trityl candesartan and their uses thereof |
| CN107709313A (en) * | 2015-06-05 | 2018-02-16 | 浙江华海药业股份有限公司 | A kind of method for preparing trityl candesartan |
| CN107709313B (en) * | 2015-06-05 | 2020-10-23 | 浙江华海药业股份有限公司 | Method for preparing trityl candesartan |
| CN109627234A (en) * | 2019-01-30 | 2019-04-16 | 浙江省食品药品检验研究院 | A kind of candesartan cilexetil crystal and preparation method thereof |
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