ZA200506290B - MEthod for the production of telmisartan - Google Patents
MEthod for the production of telmisartan Download PDFInfo
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- ZA200506290B ZA200506290B ZA200506290A ZA200506290A ZA200506290B ZA 200506290 B ZA200506290 B ZA 200506290B ZA 200506290 A ZA200506290 A ZA 200506290A ZA 200506290 A ZA200506290 A ZA 200506290A ZA 200506290 B ZA200506290 B ZA 200506290B
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- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 title claims description 41
- 238000000034 method Methods 0.000 title claims description 28
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims description 20
- 229960005187 telmisartan Drugs 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 239000002904 solvent Substances 0.000 claims description 38
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 13
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 150000002825 nitriles Chemical class 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- -1 sulphonyloxy group Chemical group 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- TTWVBVXEOQKSLK-UHFFFAOYSA-N 2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoic acid;hydrochloride Chemical compound Cl.CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O TTWVBVXEOQKSLK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 6
- 229940093476 ethylene glycol Drugs 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- 229940113088 dimethylacetamide Drugs 0.000 claims 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 2
- 239000011591 potassium Substances 0.000 claims 2
- 229910052700 potassium Inorganic materials 0.000 claims 2
- 229960004063 propylene glycol Drugs 0.000 claims 2
- 235000013772 propylene glycol Nutrition 0.000 claims 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- 241000607479 Yersinia pestis Species 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 235000011118 potassium hydroxide Nutrition 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- KSNKQSPJFRQSEI-UHFFFAOYSA-N 3,3,3-trifluoropropanoic acid Chemical compound OC(=O)CC(F)(F)F KSNKQSPJFRQSEI-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108010018961 N(5)-(carboxyethyl)ornithine synthase Proteins 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007786 electrostatic charging Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- MKNZKCSKEUHUPM-UHFFFAOYSA-N potassium;butan-1-ol Chemical compound [K+].CCCCO MKNZKCSKEUHUPM-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate 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
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YHXCWNQNVMAENQ-UHFFFAOYSA-N tert-butyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 YHXCWNQNVMAENQ-UHFFFAOYSA-N 0.000 description 1
- 230000003245 working effect Effects 0.000 description 1
Description
200s ,,
CEOS 0200
EEN
Boehringer Ingelheim Pharma GmbH & Co. KG Case 1/1482 55216 Ingelheim foreign filing text 83318fit
Process for manufacture of telmisartan
The present invention relates to a new process for preparing 4'-[2-n-propyl-4- methyl-6—(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2- carboxylic acid (INN: telmisartan).
Telmisartan is an angiotensin-ll-receptor antagonist which is suitable for the treatment of high blood pressure and other medical indications as described in EP-502314 B1. The active substance has the following structure:
H,
N CH
—
Na N HOC
LC
Oe
Telmisartan is generally prepared and sold in the form of the free acid. As disclosed in WO 00/43370, crystalline telmisartan occurs in two polymorphic forms which have different melting points. Under the influence of heat and moisture: the lower-melting polymorphic form B changes irreversibly into the higher-melting polymorphic form A.
Hitherto, telmisartan has been synthesised industrially by reacting 2-n-propyl - 4-methyl-6-(1'-methylbenzimidazol-2'-yl)-benzimidazole (1) with tert. butyl 4'- bromom-ethyl-biphenyl-2-carboxylate (Il) and subsequently saponifying according to the following Diagram 1.
Diagram 1:
Hy
N CH, Br COOCMe, 2
Besa + OC)
Oo >
CH, ® | 0)
H,
N CH,
N Nees COOCMe,
Orton wid
CH, (my
H,
N CH, \
Oe, OC
CH,
The coupling by nucleophilic substitution in the first reaction step is described in general terms in EP-502314 B1 as process b), while the saponification of the tert. butyl ester group on a laboratory scale using trifluoromethylacetic acid is described in the patent specification as Example 1. Industrially, saponification has up till now been carried out with concentrated aqueous hydrobromic acid. Scaling up the method of synthesis known from the patent specification to a large-scale industrial process was surprisingly beset with problems. Thus, the active substance prepared by the process known up till now can only be obtained in a satisfactory quality after running through a number of process steps (the crude product does not have the required purity until it has been recrystallised twice), while very long centrifuging and drying times are needed when isolating the substance. The telmisartan synthesised on an industrial scale according to Diagram 1 is obtained after working up in the form of a product which has to be subjected to a second crystallisation step to complete the purification. In the said crystallisation step, which is absolutely essential, the morphology of the end product crystallising out led to unforeseen problems.
The product precipitated in the form of long needles is difficult to filter, wash and isolate and because of the inclusion of solvent is also characterised by a very long drying time and forms large, very hard lumps «uring the drying process. Grinding up these lumps results in a dry powder which has a strong tendency to electrostatic charging and is virtually impos sible to pour.
The above-mentioned undesirable properties of a product have always proved to be a major obstacle to the large-scale production of & compound as they stop the product being manufactured reproducibly in large quantities and allow a high degree of purity to be achieved only with considerable difficulty or at additional high technical costs.
The aim of the present invention is therefore to provide an alternative method of preparing telmisartan, which can be used on a large scale and allows telmisartan to be easily worked up, purified and isolated without the disadvantages mentioned above.
Surprisingly it has been found that from a technical poi nt of view the reaction of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl)- benzimidazole
CH,
N CH,
N
Sess (1)
N{
with a compound of general formula
NC
(IV), wherein Z denotes a leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, for example a methanesulphonyloxy, phenylsulphonyloxy or : p-toluenesulphonyloxy group, to obtain the compound 2-cyano-4'-[2"-n- propyl-4"-methyl-6"-(1"-methylbenzimidazol-2"-yl)benzimidazol-1"- ylmethyilbiphuenyl
CH,
N CH
—
N NC
> N 9 v)
N{ on C which may if desired be subjected to working up (Step (a)), and su bsequent hydrolysis of the nitrile to the acid function (Step (b)) and if desired conversion of the compound (V) during working up into the hydrochloride, has considerable advantages over the synthesis shown in Diagram 1, &and in particular does not have the drawbacks mentioned above for large-scale production by the conventional method.
Step (a):
The reaction of the compound (1) with a compound of general formula (1V), wherein Z p referably denotes a halogen atom, particularly the bromine atom, is conveniertly carried out in a solvent or mixture of solvents such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane,
dimethylsulphoxide, dimethylformamide, dimethhylacetamide, dimethylformamide/tert. butanol, dimethylacetaamide/tert. butanol, toluene and benzene, optionally in the presence of an acid-binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, potacssium-tert. pentoxide, potassium tert. butoxide, potassium-n-butoxide, sodium hydride, triethylamine or pyridine, while the latter two may also be us ed as solvents, for example at a temperature between 0 and 100°C. The base is preferably used in powdered form if it is a solid.
Preferably, the reaction of the compound (I) with a compound of general formula (IV) is carried out in a solvent or mixtu re of solvents selected from dimethylsulphoxide, dimethylformamide, dimethylacetamide, dimethylformamide/tert. butanol and dimethylacetamide/tert. butanol in the presence of sodium hydroxide, potassium hydroxide or potassium tert. butoxide at a temperature between 0 and 30°C.
Particularly preferably, the reaction of the compound (I) with a compound of general formula (IV) is carried out in dimethylaacetamide or dimethylacetamide/tert. butanol in the presence of potassium hydroxide at a temperature between 0 and 20°C.
Working up:
After the reaction has ended the solvent is rermoved, for example distilled off in a water-jet vacuum, the residue is treated vwith a solvent in which the nitrile (V) has only limited solubility or is moderately soluble in the heat, for example with an alcohol such as methanol, ethanol, n- propanol, i-propanol, n-butanol or i-butanol, with an aromatic hydrocarbon such as benzene or toluene, with an ethereal solvent such as diethyl ether, tetwahydrofuran, dioxane or tert. butylmethylether, the ethereal solvents and particularly tert. butylmethylether being preferred, or with water, the crystals which may be precipitated after cooling to 10 to 20°C are suction filtered and washed first with the solvent used and then with water. If necessary the product is dried at elevated temperature, for example at 50-100°C, in a vacuum drying cupboard. The nitrile (V) is generally obtained in excellent yields between 80 and 90 % of theory and with excellent quality (purity according to HPLC > 99.5%).
Step (b):
The subsequent hydrolysis of the nitrile function into a carbo xy group is conveniently carried out in water, in an organic solvent or in a mixture of an organic solvent with water, while the organic solvent may be , for example, methamol, ethanol, n-propanol, isopropanol, tetrahydrofuran, dioxane, ethyleneglycol, propylenglycol, diglyme, dimethylsulphoxide or diethyl eneglycol monomethyl ether, in the presence of an acid such as trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulphuric acid or phosphoric acid or in the presence of a base such as lithiuma hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide or calcium hydroxide or the anhydrides thereof at temperatures betwee=n 80 and 200°C, while the water needed for the reaction may also be a constituent of one of the reagents used, e.g. one of the abovementioned aqueous acids, or may be generated under the reaction conditions from the reagen ts, possibly from one of the above-mentioned alkali metal hydroxides.
Preferably, the hydrolysis of the nitrile function is carried o ut in a high-boiling solvent system selected from ethyleneglycol/water and proppyleneglycol/water, in the presence of a base, potassium hydroxide being particularly suitable, at temperatures between 140 and 200°C, particularly at a termperature between 155 and 185°C.
Working up:
After the reaction has ended the solvent is removed, for example distilled off in a water-jet vacuum, the residue is diluted with water and taken up in hydrochloric acid, for example with 5 to approx. 32% (conc) hydrochloric acid, preferably with 5 to 20% hydrochloric acid, whereupon telmaisartan hydrochloride crystallises out. The crystal suspension is cooled to 10 to 25°C if nec essary and may be stirred at this temperature for a ce=rtain length of time, for example up to 3 hours. After the crystals have been suction filtered they are washed with water amd if necessary dried in a vacuum drying cupboard at elevated temperature, for example at 50 to 120°C.
Telmisartan in acid form can be liberated from the telmisartan hydrochloride in the usual way, e.g. by titratiom with aqueous alkali metal hydroxide solution.
For example, the acid form is liberated analogously to the method described in WO 0043370 (page 3, line 6 top. 4, line 38, and Examples 1 to 3).
For large-scale production the process according to the invention has the following advantages inter ali a deserving special mention: e compounds of formula (IV), particularly 4'-bromomethyl-2-cyanobiphenyl, are mass-produced and may be obtained cheaply; e the coupling of components (I) and (IV) according to Step (a) may be carried out in a high concentration and at a correspondingly high throughput, while working up particularly using tert. butylmethylether yields the nitrile (V) as a precipitate which is easy to filter and wash, thus dispensing with the need for additional laborious working up procedures; e the nitrile (V) is obtained i n excellent yields of between 80 and 90 % of theory and with excellent quality (purity according to HPLC > 99.5%); e the saponification of the nitrile (V) in Step (b) also produces excellent yields > 95% of theory; ¢ the end product telmisartain may be isolated either as an ampholyte or, preferably, by precipitatio n with hydrochloric acid as a hydrochloride which is easy to filter and hence easy to purify.
The following procedure is used, in a particularly preferred manner according to the invention:
Step (a): All the quantities specified relate to a batch size of 0.1 mol of the compound (1) and if the batch size is altered must be multiplied by a corresponding factor.
50 to 200 ml solvent, preferably 80 to 120 mi, per 0.1 mol of the compound (l) are placed in a suitably dimensioned reaction vessel, the compound (|) is suspended in the solvent and 0.1 to 0.2 mol of base, preferably 0.102 to 0.12 mol, are added batchwise thereto with stirrin g, while the temperature is maintained at between 10 and 50°C, preferably 15 to 30°C, and when the exothermic reaction has ended stirring may be continued for up to another 3 hours at this temperature. The mixture is cooled to approx. 0 - 10°C, for example approx. 5°C, and then a mixture of 0.1 to 0.2 mol of a compound of general formula (IV), preferably 0.100 to 0.1 2 mol, with 50 to 200 ml solvent (per 0.1 mol of the compound (IV)) is added dropwise at 10 to 30°C, preferably at approx. 20°C. The reaction mixture is optionally maintained at approx. 0 to 20°C, preferably 5 to 10°C, by cooling with the ice bath. Then it may be rinsed out with a few ml of solvent a nd stirred for up to another 3 hours at 0 to 20°C.
In another embodiment the base is placed in 30 to 100 ml! solvent, preferably dimethylformamide, dimethylacetamide, dimethylformamide/tert. butanol or dimethylacetamide/tert. butanol, at 10 to 30°C, stirred for up to an hour at about 20°C, for example, and then a suspension of the compound (1) in 30 to 100 ml solvent is slowly metered in at this temperature. All the other steps are the same as in the previous embodiment. The solvent mixtures specified are used in a ratio by volume of amide : tert. butanol = 10: 1t0 2.5: 1, for example 5: 1.
Working up:
The solvent is conveniently largely distilled off under reduced pressure, for example under a water-jet vacuum, whereu pon the product crystallises out.
After the residue has cooled to approx. 40 to 80°C, preferably about 60°C, it is diluted with 100 to 300 ml solvent (per 0.1 mmol batch size, based on compound (1), preferably tert. butyimethylether, and stirred for up to 5 hours without any input of energy. The mixture is cooled to 0 to 30°C, preferably 15 to 20°C, and stirred for up to a further 5 hours at this temperature. The crystals are suction filtered and washed batchwise with 50 to 150 ml of the solvent a_nd then with 200 to 300 ml of water. The product is dried ir the vacuum «irying cupboard at 50 to 100°C, preferably about 60°C.
Step (b)= Unless otherwise stated, all the amounts specified are ba sed on a batch size of 0.05 mol of the compound (V) and must be multiplied by a corresponding factor if the batch size is altered. 0.05 mol of the compound (V), 200 to 300 mi of the organic solvent, 0.5to0 5 ml of wa-ter and 0.3 to 0.5 mol of the base are combined and heated to the boiling temperature of the solvent system used, i.e. if the preferred ethylene-glycol/water mixture is used, it is heated to 140 to 200 °C, preferably to 155 to 185°C. The mixture is stirred for up to 24 hours at this ternperature.
In another embodiment 0.361 mol of the nitrile (V) are placed in 1.510 2 L of the orga nic solvent, preferably ethyleneglycol, 25 to 50 mi of water and 2.5to 3 mol of the base are added and the mixture is heated to 140 to 2€0 °C, preferabely to 155 to 185°C, for up to 24 hours, with stirring. All the «ther steps correspond to those in the previous embodiment.
Workings up:
The amounts given are based on a batch size of 0.05 mol of comp ound (V).
The solwent is conveniently eliminated under reduced pressure, for example distilled off under a water jet vacuum, the residue is diluted with 30 to 100 ml of water, preferably about 5 ml, and stirred into a mixture of 100 to 150 ml of water (preferably about 125 mi) and 40 to 60 ml (preferably about 50 ml) conc. hydrochloric acid (approx. 32%), possibly rinsing with water. The telmisartan hydrochloride that crystailises out is cooled to 10 to 25 °C and is stirred feor up to 3 hours at this temperature. After the crystals haves been suction filtered they are washed with 50 to 200 ml of water and dried at 50 to 120°C im a vacuum drying cupboard.
The Examples that follow serve to illustrate the invention and relate to exemplifying embodiments of the methods of synthesis according to the invention for preparing telmisartan, but without restricting the invention to their contents.
Example 1 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"'-methylbenzismidazol-2"'- yl)benzimidazol-1"-ylmethyllbiphenyl 32.24 g of 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl)-benzimidazole x H20 are placed in 100 ml of dimethylacetamide (DNA), 11.8 g of potassium tert. butoxide are added batchwise with stirring at approx. 20°C and then the mixture is stirred for one hour at about 20°C. The mixture is cooled to 5°C and then a mixture of 28.6 g of 4-bromomethyl-2'-cyano-biphenyl and 95 ml of
DMA (dissolved at approx. 20°C) is added dropwise over about 30 minutes.
The temperature of the reaction mixture is maintained at approx. 5 — 10°C by cooling with the ice bath. Then it is rinsed with 5 ml oof DMA and stirred for a further 1.5 hours at 5 — 10°C.
The solvent is largely distilled off under a water jet vacuum, during which time the product crystallises out. The residue is cooled to 60°C, diluted with 230 mi of tert. butylmethylether and stirred for 1 hour without any energy input, then cooled to 15 — 20°C and stirred for another hour at this temperature. The crystals are suction filtered, washed batchwise with 100 ml of tert. butylmethylether, then with 250 ml of water and there dried in a vacuum drying cupboard at 80°C.
Yield: 43.3 g (87.5% of theory).
Melting point:196 — 197°C
HPLC: > 99.9 %
Example 2 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"'-methylbenzimidazol-2"- yl)benzimidazol-1"-yimethyllbiphenyl 32.24 g of 2-n-propyl-4-methyl-6-(1'-methylbenzimid azol-2'-yl)-benzimidazole x H20 are placed in 100 ml of DMA, 6.9 g of potassium hydroxide (powder)
are added batchwise with stirring at approx. 20°C and then stirred for one hour at about 20 to 25°C. The mixture is cooled to 5°C and then 28.6 g of 4- bromomethy#-2'-cyano-biphenyl in 95 ml of DMA (dissolved at approx. 20°C) are added dropwise over approx. 30 minutes. The temperature of the reaction mixture is maintained at approx. 5 — 10°C by cooling with the ice bath. Then it is rinsed with 5 ml of DMA and stirred for a further 1.5 hours at 5 — 10<°C.
The solvent is largely distilled off under a water jet vacuum, during wheich time the product crystallises out. The residue is cooled to 60°C, diluted with 225 mi of tert. butylrmethylether and stirred for 1 hour without any energy input, then cooled to 15 — 20°C and stirred for another hour at this temperature. The crystals are suction filtered, washed batchwise with 100 ml of tert. butylmethylether, then with 250 ml of water and then dried in a vacuum drying cupboard at 80°C.
Yield: 40.45 g (81.7% of theory).
Melting point:196 — 197°C
HPLC: >99.9%
Example 3 2-cyano-4'-[ 2'-n-propyl-4"-methyl-6"-(1""-methylbenzimidazol-2"- y)benzimidazol-1"-yimethyllbiphenyl 6.9 g of potassium hydroxide (powder) are placed in 50 ml of DMA, stirred for minutes at 20 to 25°C and then a suspension of 32.24 of 2-n-propsy!-4- methyl-6-(1"-methylbenzimidazol-2'-yl)-benzimidazole x HO in 50 mi of DMA is metered in at 20 to 25°C. After it has all been added the vessels awe rinsed with 10 ml of DMA and then stirred for another hour at 20 to 25°C. The mixture is c ooled to 5°C and then 28.6 g 4-bromomethyl-2'-cyano-biphenyl in 95 ml of DNA (dissolved at approx. 20°C) are metered in. The temperature of the reactior mixture is maintained at approx. 5 — 10°C by cooling wit h the ice bath. Then itis rinsed with 5 ml of DMA and stirred for a further hour at 5 — 10°C.
The solvent is largely distilled off under a water jet vacuum, during which time the product crystallises out. The residue is c ooled to 60°C, diluted with 250 ml of tert. butylmethylether and stirred for 2 hours without any input of energy.
The crystals are suction filtered, washed batchwise with 100 ml of tert. butylmethylether, then with 250 mi of water and then dried in a vacuum drying cupboard at 80°C.
Yield: 43.37 g (87.5% of theory).
Meiting point:196 — 198°C
HPLC: 99.1 %
Example 4 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"'-methylbenzimidazol-2"'- yhbenzimidazol-1"-ylimethylbiphenyl 53.4 g of potassium hydroxide (powder) ares placed in 385 mi of DMA and then a suspension of 248.25 g of 2-n-propyll-4-methyl-6-(1'- methylbenzimidazol-2'-yl)-benzimidazole x H;O in 385 ml of DMA are metered in at 20 to 25°C. After it has all been added the vessels are rinsed with 77 mi of DMA and then stirred for another hour at 20 to 25°C. The mixture is cooled to 5°C and then 209.5 g of 4-bromomethyl-2'-cyano-biphenyl in 731.5 ml of
DMA (dissolved at approx. 20°C) are metered in. The temperature of the reaction mixture is maintained at approx. 5 — 10°C by cooling with the ice bath. Then it is rinsed with 38.5 ml of DMA and stirred for a further hour at 5 — 10°C.
The solvent is largely distilled off under a wrater jet vacuum, during which time the product crystallises out. The residue is cooled to 60°C, diluted with 1925 ml tert. butylmethylether and stirred for 2 hours without any energy input. The crystals are suction filtered, washed batchwvise with 770 ml of tert. butyimethylether/DMA = 9:1, then with 192 § ml of water and twice with 250 ml of tert. butyimethylether and then dried at 80°C in a vacuum drying cupboard.
Yield: 322.15 g (84.4% of theory).
Melting point: 197 — 198.5°C
HPLC: 99.6%
Example 5: Telmisartan x HCI 25 g of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1""-methylberzimidazol-2"'- yl)benzimidazol-1"-yImethyl]biphenyl, 250 mi of ethyleneglwycol, 0.9 ml of water and 24.75 g of caustic potash (>85%) are combined and h €ated to 160°C with stirring. The mixture is stirred for 13.5 hours at this temperature.
The solvent is largely distilled off under a water jet vacuum, the residue is cooled to 100°C, diluted with 50 ml of water and stirred into a mixture of 125 ml of water and 50 ml of conc. hydrochloric acid (approx. 32%), rinsing with 50 mi of water. The telmisartan hydrochloride that crystallisses out is cooled to to 20°C and stirred for approx. 1 hour at this temperatu re. After the crystals have been suction filtered they are washed with 100 ml of water and dried ina vacuum drying cupboard at 100°C.
Yield: 27.3 g (98.2% of theory).
HPLC: 99.9%.
Example 6: Teimisartan x HCI 179 g of 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1"-methylbenzimidazol-2"'- yl)benzimidazol-1"-ylmethyllbiphenyl are placed in 1611 ml of ethyleneglycal, 32.5 ml of water and 178.7 g of potassium hydroxide (powrder) are added and the mixture is heated to 150 to 160°C with stirring. The mixture is stirred for approx. 15 hours at this temperature and then cooled to 100°C.
The solvent is largely distilled off under a water jet vacuunn, the residue is cooled to 100°C, diluted with 358 ml of water and stirred imto a mixture of 716 ml of water and 358 ml of conc. hydrochloric acid (approx. 32%), rinsing with 179 ml of water. The telmisartan hydrochloride that crysta llises out is stirred for one hour at 60°C, cooled to 15 to 20°C and stirred for approx. 1 more hour at this temperature. After the crystals have been suction fi ltered they are washed with 716 ml of water and dried in a vacuum drying cupboard at 100°C.
Yield: 192.1 g (96.5% of theory).
HPLC: >99.9% 5.51 g of telmisartan x HCI are dissolved in 50 ml of 40% acetic acid while refluxing. Then the brown solution is filtered hot through 1.1 g of charcoal, washed with 2.5 ml of 40% acetic acid and 2.5 ml of 4N NaOH are added dropwise to the light brown filtrate with stirring at 80 — 90°C. The telmisartan crystallises out, the suspension is dilated with 30 ml of water and slowly cooled to ambient temperature. The telmisartan is suction filtered and washed with 50 ml of water. The telmisartan is dried at 80°C in a vacuum drying cupboard.
Yield: 4.80 g (93.3% of theory)
Claims (17)
1. Process for preparing telmisartan, wherein (a) 2-n-propyl-4-methyi-6-(1'-methylbenzirnidazol-2'-yl)-benzimidazole CH, N CH, AS Pests (1 N, is reacted with a compound of general formula z NC Iv), wherein Z denotes a leaving group, and the resulting compound is worked up, if desired, (b) the cyano group of the compound 2-cyano-4'-[2"-n-propyi-4"-methyl-6"- (1"-methylbenzimidazol-2""-yl)benzimida zol-1"-ylmethyl]biphenyl thus obtained CH, N CH — N NC 1 Oh NQ o Oo is then converted by hydrolysis into the acid function and if desired the telmisartan thus obtained is converted into the hydrochloride during working up.
2. Process according to claim 1, characterise=d in that Z denotes a halogen atom, preferably the bromine atom, or a substituted sulphonyloxy group.
3. Process according to claim 1, characterisexd in that step (a) is carried out in a solvent or mixture of solvents selected fromm methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide, dimethylacetamide, dimethylformamide/tert. butanol, dimethylacetamide/tert. butanol, toluene and benzene, optionally in t he presence of an acid-binding agent.
4. Process according to claim 3, characterised in that the acid-binding agent is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, po-tassium methoxide, potassium tert.pentoxide, potassium tert. butoxide, potaxssium-n-butoxide, sodium hydride, triethylamine and pyridine.
5. Process according to one of claims 1 to 4 , characterised in that step (a) is carried out at a temperature between 0 and 100°C.
6. Process according to one of claims 1 to 5, characterised in that in step (a) the reaction of the compound (1) with a compound of general formula (IV) is carried out in a solvent or mixture of solvents selected from dimethylsulphoxide, dimethylformamide, dimnethylacetamide, dimethylformamide/tert. butanol and dimeth ylacetamide/tert. butanol in the presence of sodium hydroxide, potassium haydroxide or potassium tert. butoxide at a temperature between 0 and 3€Q°C.
7. Process according to one of claims 1 to 6, characterised in that after step (a) has been carried out the solvent is removed, the residue is treated with a solvent in which the nitrile (V) has only limited solubility or is moderately soluble in the heat, the crystals optionally p recipitated after cooling are suction filtered and optionally washed and if desired the product is dried at elevated temperature.
8. Process according to claim 7, characterised in that the solvent for treating the residue is an alcohol, an aromatic hydrocarbon, an ether or water.
9. Process according to one of claims 1 to 8, characterised in that the hydrolysis of the nitrile function in step (b) is carried out in water, in an organic solvent or in a mixture of an organic solvent with water in the presesnce of an acid or a base at temperatures between 80 and 200°C.
10. Process according to claim 9, characterised in that the organic solvent is methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, dioxane, ethyleneglycol, propyleneglycol, diglyme, dimethylsulphoxide or diethyleneglycol monomethyl ether.
11. Process according to one of claims 9 or 10, characterised in that the hydrolysis is carried out in the presence of an acid selected from trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulphuric acid and phosphoric acid.
12. Process according to one of claims 9 or 10, characterised in that the hydrolysis is carried out in the presence of a base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide and calcium hy droxide or the anhydrides thereof.
13. Process according to one of claims 9, 10 or 12, characterised im that the hydrolysis is carried out in a high-boiling solvent system selected from ethyleneglycol/water and propyleneglycol/water in the presence of a base, preferably potassium hydroxide, at temperatures between 140 andl 200 °C, particularly at a temperature between 155 and 185°C.
14. Process according to one of claims 1 to 13, characterised in th.at for the working up according to step (b) the solvent is eliminated, the residue is optionally diluted with water and taken up in aqueous hydrochloric acid, the telmisartan hydrochloride that crystallises out is cooled if necessary, then suction filtered and optionally dried.
15. Process according to claim 14, characterised in that telmisartan hydrochloride is converted into the acid form.
18a
16. Process according to claim 1, substantially as herein described and exemplified.
17. Telmisartan when prepared by the process of any one of the preceding claims. AMENDED SHEET
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