WO2018078657A1 - Process for preparation of glipizide - Google Patents
Process for preparation of glipizide Download PDFInfo
- Publication number
- WO2018078657A1 WO2018078657A1 PCT/IN2017/050501 IN2017050501W WO2018078657A1 WO 2018078657 A1 WO2018078657 A1 WO 2018078657A1 IN 2017050501 W IN2017050501 W IN 2017050501W WO 2018078657 A1 WO2018078657 A1 WO 2018078657A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glipizide
- solvent
- solution
- cyclohexylcarbamoyl
- tert
- Prior art date
Links
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 title claims abstract description 117
- 229960001381 glipizide Drugs 0.000 title claims abstract description 111
- 238000000034 method Methods 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 87
- 238000006243 chemical reaction Methods 0.000 claims description 80
- 239000002904 solvent Substances 0.000 claims description 65
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 46
- -1 alkali metal alkoxide Chemical class 0.000 claims description 45
- NYLHFSLGOJDWNQ-UHFFFAOYSA-N n-[4-(2-azaniumylethyl)phenyl]sulfonyl-n'-cyclohexylcarbamimidate Chemical compound C1=CC(CCN)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 NYLHFSLGOJDWNQ-UHFFFAOYSA-N 0.000 claims description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- CRBOSZMVDHYLJE-UHFFFAOYSA-N methyl 5-methylpyrazine-2-carboxylate Chemical compound COC(=O)C1=CN=C(C)C=N1 CRBOSZMVDHYLJE-UHFFFAOYSA-N 0.000 claims description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 27
- 229910052783 alkali metal Inorganic materials 0.000 claims description 22
- AKUPRXWQEIRZBC-UHFFFAOYSA-N tert-butyl n-[2-(4-sulfamoylphenyl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCC1=CC=C(S(N)(=O)=O)C=C1 AKUPRXWQEIRZBC-UHFFFAOYSA-N 0.000 claims description 21
- RBYJWCRKFLGNDB-UHFFFAOYSA-N 5-methylpyrazine-2-carboxylic acid Chemical compound CC1=CN=C(C(O)=O)C=N1 RBYJWCRKFLGNDB-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 14
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 13
- 235000011181 potassium carbonates Nutrition 0.000 claims description 13
- 125000005907 alkyl ester group Chemical group 0.000 claims description 12
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 claims description 12
- FXNSVEQMUYPYJS-UHFFFAOYSA-N 4-(2-aminoethyl)benzenesulfonamide Chemical compound NCCC1=CC=C(S(N)(=O)=O)C=C1 FXNSVEQMUYPYJS-UHFFFAOYSA-N 0.000 claims description 11
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 7
- 235000017550 sodium carbonate Nutrition 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003610 charcoal Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- DEDJQZNLAXYJBT-UHFFFAOYSA-N 3-methylpyrazine-2-carboxylic acid Chemical compound CC1=NC=CN=C1C(O)=O DEDJQZNLAXYJBT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims 1
- 229910052808 lithium carbonate Inorganic materials 0.000 claims 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- IMEZLHZLIANIAS-UHFFFAOYSA-N 5-methyl-n-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(N)(=O)=O)C=C1 IMEZLHZLIANIAS-UHFFFAOYSA-N 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QBTHZBYYZUTCNC-UHFFFAOYSA-N 3,5-dimethylpyrazine-2-carboxylic acid Chemical compound CC1=CN=C(C(O)=O)C(C)=N1 QBTHZBYYZUTCNC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 231100001261 hazardous Toxicity 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229940088991 glucotrol Drugs 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- MUAUTBNKPSNTFM-UHFFFAOYSA-N 2-phenylethyl carbamate Chemical compound NC(=O)OCCC1=CC=CC=C1 MUAUTBNKPSNTFM-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- ZBULFWLJSYSQEV-UHFFFAOYSA-N 6-methyl-n-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide Chemical compound CC1=CN=CC(C(=O)NCCC=2C=CC(=CC=2)S(N)(=O)=O)=N1 ZBULFWLJSYSQEV-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- LMHUNBZOUPHIHJ-UHFFFAOYSA-N N-ethyl-N-(4-sulfamoylphenyl)pyrazine-2-carboxamide Chemical compound N1=C(C=NC=C1)C(=O)N(C1=CC=C(C=C1)S(=O)(=O)N)CC LMHUNBZOUPHIHJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical class NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 229940127208 glucose-lowering drug Drugs 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- ZHRCZKUJOVABOW-UHFFFAOYSA-N n-cyclohexyl-2-sulfamoylbenzamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C(=O)NC1CCCCC1 ZHRCZKUJOVABOW-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CXROVLGVIPCDQZ-UHFFFAOYSA-N tert-butyl N-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]carbamate Chemical compound C1(CCCCC1)NC(=O)NS(=O)(=O)C1=CC=C(C=C1)CCNC(OC(C)(C)C)=O CXROVLGVIPCDQZ-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to process for preparation of Glipizide.
- Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.
- the chemical name of Glipizide is l-cyclohexyl-3-[[p-[2-(5-methylpyrazine carboxamido) ethyl]phenyl] sulfonylurea.
- the molecular formula is C2iH27Ns0 4 S, molecular weight is 445.55; the structural formula is shown below:
- Glipizide is commercially marketed as Glucotrol.
- Glucotrol is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- US3669966 disclose benzenesulphonylurea compounds and processes of their preparation.
- the process for preparing Glipizide disclosed in this patent involves reacting 5-methyl pyrazine-2- carboxylic acid with ethyl chloroformate in the presence of triethylamine followed by reacting with p-(4-amino-ethyl) benzene sulphonamide to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine- carboxamide.
- the crude product is then purified by crystallization from ethanol- water.
- N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine- carboxamide is further reacted with cyclohexyl isocyanate in the presence of base to obtain Glipizide.
- Another process disclosed in this patent involves reaction of methyl pyrazine carboxylic acid with thionyl chloride to form corresponding acid chloride followed by reacting the acid chloride with p-(4-amino-ethyl) benzene sulphonamide to obtain N (2-(4-(aminosulfonyl)phenyl) ethyl pyrazine carboxamide.
- Indian patent application 2742/MUM/2013 disclosed preparation of Glipizide comprising a) preparing ester of 5-methylpyrazine-2-carboxylic acid by reacting 5- methylpyrazine-2-carboxylic acid in presence of alcohol and thionyl chloride (SOCb) at temperature 25-40°C; b) reacting ester of 5-methylpyrazine-2- carboxylic acid with 4-(2-aminoethyl)-benzene sulphonamide at 60-80°C to get 5- methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide; c) reacting 5- methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide with cyclohexyl isocyanate in presence of potassium carbonate and mixture of organic solvents to prepare Glipizide. Further it is disclosed that Glipizide is purified using mixture of
- CN102993106 disclosed synthesis of Glipizide which comprised of following reaction scheme.
- the present invention provides a simple, consistent, high yielding and industrially viable process for preparation of Glipizide. Object of invention
- An object of the invention is to provide new process for preparation of highly pure Glipizide.
- Another object of the invention is to provide a simple, economic, consistent process for preparation of highly pure Glipizide with easy work-up procedure.
- Yet another object of the invention is to provide a commercially viable and industrially applicable process for preparation of highly pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
- Figure 1 It represents HPLC chromatogram of Blank.
- Figure 2 It represents HPLC chromatogram of Glipizide as obtained in Example 5.
- Figure 3 It represents HPLC chromatogram of pure Glipizide as obtained in Example 10. Summary of invention
- the present invention provides a simple, economic, consistent, industrially feasible process for the preparation of Glipizide.
- the present invention provides a process for preparation of Glipizide in a high yield and high purity for pharmaceutical use.
- the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate optionally in a solvent to obtain Glipizide in high yield and high purity.
- the present invention provides a process for preparation of Glipizide comprising
- tert-butyl 4-sulfamoylphenethylcarbamate a) reacting 4-(2-aminoethyl)benzene sulfonamide and di-tert-butyl dicarbonate in presence of solvent to obtain tert-butyl 4-sulfamoylphenethylcarbamate; b) reacting tert-butyl 4-sulfamoylphenethyl carbamate with cyclohexyl isocyanate in presence of alkali carbonate and solvent to obtain tert-butyl 4-(N- (cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate;
- the present invention provides a process for purification of Glipizide to obtain Glipizide in purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
- the present invention provides a process for preparation of Glipizide in a high yield and high purity.
- impurities found in Glipizide. These impurities are determined by liquid chromatography according to the protocol described in the USP. Identified impurities comprise the following impurities: Compound A namely [N- ⁇ 2-[(4- aminosulfonyl)phenyl]ethyl ⁇ -5-methyl-pyrazinecarboxamide], Compound B namely [6-methyl-N-[2-(4-sulfamoyl phenyl) ethyl]pyrazine-2-carboxamide] and Compound C namely [l-cyclohexyl-3-[[4-[2-[[(6-methyl pyrazin-2-yl)carbonyl] amino]ethyl]phenyl] sulfonylurea] .
- the levels of the impurities of Glipizide of the present invention as obtained in crude and pure forms are as provided below. Even in crude form, the purity is at least 90 % and preferably above 95%. Table 1
- Figures 2 and 3 represent chromatograms of crude and pure Glipizide prepared according to example 5 and example 10 respectively of the present application.
- the inventors of the present invention have successfully arrived at pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
- the total impurities are restricted at less than 1.5 %, preferably less than 1.0% and most preferably less than 0.5%.
- Glipizide prepared according to this process comply with both USP and ICH requirements.
- the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of alkali metal alkoxide optionally in a solvent to obtain Glipizide in high yield.
- the alkyl ester of 5-methyl pyrazine-2-carboxylic acid is methyl 5-methylpyrazine- 2-carboxylate.
- the alkali metal alkoxide is selected from the group consisting of sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, or mixtures thereof.
- the solvent used is alcohol for example methanol, ethanol, isopropanol, propanol and n-butanol.
- reaction Scheme 1 A first aspect of the present invention is represented by reaction Scheme 1 as below:
- the process represented in scheme 1 comprises treating 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide with alkyl ester of 5 -methyl pyrazine- 2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate preferably sodium methoxide.
- base selected from alkali metal alkoxide or alkali metal carbonate preferably sodium methoxide.
- the mixture is stirred and heated at temperature 25-100°C.
- the reaction is monitored by TLC or HPLC. It takes around 30 mins to 5 hrs for completion.
- a second lot of alkyl ester of 5 -methyl pyrazine-2-carboxylic acid and sodium methoxide solution is added to the mixture for the completion of reaction.
- ratio of first lot to second lot for sodium methoxide is from at least 10: 1, preferably at least 15: 1 and ratio of first lot to second lot for methyl ester is at least 5: 1.
- water is added to the reaction mass and the reaction mass was acidified using hydrochloric acid. The mass is stirred for 1-2 hr to obtain solid Glipizide.
- the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of sodium methoxide at temperature in the range of 25-100°C for the period of from 30 min to 5 hours to obtain Glipizide in high yield.
- the present invention provides a process for preparation of Glipizide comprising heating a mixture of 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and methyl 5-methylpyrazine-2- carboxylate in presence of sodium methoxide solution.
- a mixture of 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and methyl 5-methylpyrazine-2- carboxylate in presence of sodium methoxide solution.
- powdered sodium methoxide in a solvent can be used.
- the reaction temperature is 50-90°C and reaction time is around 1-2 hr.
- sodium methoxide is in the form of 25% sodium methoxide solution in methanol.
- the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of alkali metal carbonate and suitable solvent to obtain Glipizide.
- the alkali metal carbonate is selected from the group consisting of potassium carbonate (K2CO3), sodium carbonate (Na 2 C03), potassium bicarbonate (KHCO3) and sodium bicarbonate (NaHC0 3 ).
- the solvent used is selected from the group consisting of toluene, acetonitrile, isopropanol, methanol, DMF or mixtures thereof.
- the reaction is carried out at temperature in the range of 25-100°C.
- the reaction is carried out for 4-40hrs.
- the reaction of 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine-2-carboxylic acid is carried out in presence of alkali metal carbonate for example potassium carbonate and solvent for example toluene.
- alkali metal carbonate for example potassium carbonate
- solvent for example toluene.
- the reaction mixture was stirred at refluxed temperature and maintained for 15-20hrs. After completion of reaction the solvent is distilled off from the reaction mixture.
- the mass is cooled to ambient temperature and water is added to the mass.
- the pH of reaction mass was brought to below 2.0 using acid for example dilute hydrochloric acid to obtain solid of Glipizide. Glipizide so obtained is then purified to get pure Glipizide.
- the present invention provides a process for preparation of Glipizide comprising the steps of 1) reacting methyl 5-methylpyrazine-2-carboxylic acid (8) with acid in presence of solvent to obtain methyl 5-methylpyrazine-2-carboxylate (9);
- the acid used in step 1) is sulphuric acid.
- the solvent used in step 1) is methanol.
- step 1) is carried at 40-60°C for a period of 1 to 5hrs.
- Methyl 5-methylpyrazine-2-carboxylate used in step 2) can also be prepared by processes reported in the art.
- the alkali metal alkoxide used in step 2) is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, potassium methoxide and sodium methoxide. Preferably sodium methoxide is used.
- the alkali metal carbonate used in step 2) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
- step 2) is carried out at temperature in the range of 25-100°C optionally in a solvent.
- alkali metal alkoxide is used as base in step 2) the reaction is carried out for 30min to 5hr.
- alkali metal carbonate is used as base in step 2) the reaction is carried out for 4 to 40 hours.
- the solvent used is selected from toluene, acetonitrile, isopropanol, methanol, DMF or mixtures thereof.
- reaction Scheme 2 The second embodiment of the present invention is represented by reaction Scheme 2.
- the process as represented in scheme 2 comprises the following steps:
- step b) treating 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate as obtained in step a) in presence of alkali metal alkoxide for example sodium methoxide solution or alkali metal carbonate for example sodium carbonate or potassium carbonate.
- alkali metal alkoxide for example sodium methoxide solution
- alkali metal carbonate for example sodium carbonate or potassium carbonate.
- the reaction is carried out in presence of solvent.
- the reaction mixture is stirred and heated at temperature 80-90°C. After completion of reaction, water is added to the reaction mass and the reaction mass is acidified using hydrochloric acid. The mass is stirred for 1-2 hr to obtain solid of Glipizide.
- the present invention provides a process for preparation of Glipizide comprising 1) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzenesul fonamide (7);
- the process as represented in scheme 3 comprises:
- Methyl 5-methylpyrazine-2-carboxylate as used in step b) is prepared by the procedures described in one or more embodiment of the present invention or it can be prepared by the processes reported in the art.
- the present invention provides a process for preparation of Glipizide comprising
- the process as represented in scheme 4 comprises the steps of a) treating tert-butyl 4-sulfamoylphenethylcarbamate with potassium carbonate in presence of solvent for example acetone.
- the reaction mixture is heated to 50-55°C and cyclohexylisocyanate is added to it.
- the mixture is stirred for 2-6hr.
- the reaction mass is filtered and washed with solvent for example acetone or water or their mixture.
- the filtrate is acidified using acid for example hydrochloric acid to give solid of tert-butyl 4-(N-
- step b) tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate obtained in step a) dissolved in solvent for example methanol and the solution is treated with acid for example hydrochloric acid at 50-55°C.
- the mass is treated with alkali for example sodium hydroxide to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide or tert-butyl 4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate is deprotected by methods known in the prior art;
- alkali for example sodium hydroxide
- step b) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide as obtained in step b) with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide for example sodium methoxide to obtain Glipizide;
- the present invention provides a process for preparation of Glipizide comprising
- the process as represented in scheme 5 comprises the steps of a) treating 4-(2-aminoethyl)benzenesulfonamide with di-tert-butyl dicarbonate in presence of solvent for example dimethylformamide for 2- 6hr at ambient temperature. After completion of reaction, water is added to the reaction mass and stirred the mixture for lhr to obtain solid of tert-butyl 4-sulfamoylphenethylcarbamate;
- the mass is treated with alkali for example sodium hydroxide to obtain 4-(2- aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulphonamide and d) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide as obtained in step c) with methyl 5-methylpyrazine-2-carboxylate ester in presence of alkali metal alkoxide for example sodium methoxide to obtain Glipizide.
- alkali for example sodium hydroxide
- the present invention provides a process for preparation of Glipizide comprising i) reacting 4-(2-aminoethyl)benzenesulfonamide (2) and di-tert-butyl decarbonate (3) in presence of solvent to obtain tert-butyl 4- sulfamoylphenethylcarbamate (4);
- the present invention provides a process for purification of Glipizide to obtain Glipizide in high purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
- step b) optionally treating the solution of step b) with charcoal and filtering the solution
- step d) cooling the solution of step d) to obtain pure Glipizide.
- the first solvent is selected from the group selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide and N-methylpyrrolidone.
- the heating is carried out at 50-100°C.
- the second solvent is alcohol selected from methanol, ethanol, isopropanol, propanol, n-butanol and water, or mixtures thereof.
- the process of purification of Glipizide involves, dissolving crude Glipizide in first solvent for example dimethylformamide to get a solution.
- Second solvent for example methanol. ethanol, isopropanol, n-butanol, preferably methanol is added to the filtrate at 50-
- step b) heating the solution at 50° to 70°C c) treating the solution of step b) with charcoal and filtering the solution d) adding methanol to the solution
- step d) cooling the solution of step d) to obtain pure Glipizide.
- Glipizide obtained according to the present invention is having purity more than 99%.
- a process for preparing highly pure Glipizide comprising the steps of a) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide to obtain Glipizide; b) purifying Glipizide by heating a solution of Glipizide in dimethylformamide at 50° to 90°C, treating the solution with charcoal and filtering the solution, adding methanol to the solution and cooling the solution to obtain pure Glipizide having high purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
- the present process is suitable for scale up production of Glipizide as it involves easy work up procedure and the reaction steps.
- the present process avoids the use of hazardous reagents like thionyl chloride, ethyl chloroformate.
- the present process avoids reaction conditions like reactions at low temperature for example below 0°C and high temperature which saves energy.
- the present process avoids use of expensive coupling reagents like 1- hydroxybenzotriazole, ⁇ , ⁇ '-dicyclohexylcarbodimide, 1 -ethyl - (3- dimethylaminopropyl) carbodiimide hydrochloride (EDC HC1).
- tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (60g, 0.19moles), potassium carbonate (41.4g, 0.29moles) and acetone (250ml) were mixed.
- the mixture was heated to 50-55°C.
- Cyclohexylisocyanate (27.5g, 0.21moles) was added slowly to the mixture and the mass was stirred for 3hr at the same temperature. Again, a second lot of cyclohexylisocyanate (0.6moles) and potassium carbonate (0.9moles) was added to the reaction mixture.
- reaction mixture was cooled to 25°C to 35°C and water (125ml) was added to it.
- the mixture was acidified using diluted hydrochloric acid to precipitate out the solid.
- the solid obtained was filtered, washed with water (2x25ml) and dried to afford Glipizide (29g).
- reaction mixture was cooled to 25 °C to 35°C and water (25ml) was added to it.
- the mixture was acidified using diluted hydrochloric acid to precipitate out the solid.
- the solid obtained was filtered, washed with water (10ml) and dried to afford Glipizide (5.6g).
- Glipizide 55 g was dissolved in dimethylformamide (250ml). The solution was heated at 55°C and stirred for lOmin. The mixture was treated with activated charcoal (2.75g) and filtered the solution. Methanol (660ml) was added to the filtrate at 55°C and the mixture was stirred for 1 hr at the same temperature. The precipitate obtained was filtered, washed with methanol (50ml) and unloaded.
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Abstract
The present invention discloses a simple, economic, consistent, commercially viable and industrially applicable process for preparation of Glipizide in high yield and highly pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
Description
PROCESS FOR PREPARATION OF GLIPIZIDE Field of invention
The present invention relates to process for preparation of Glipizide.
Background of invention Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class. The chemical name of Glipizide is l-cyclohexyl-3-[[p-[2-(5-methylpyrazine carboxamido) ethyl]phenyl] sulfonylurea. The molecular formula is C2iH27Ns04S, molecular weight is 445.55; the structural formula is shown below:
Various patents in the art disclose process for preparation of Glipizide.
US3669966 disclose benzenesulphonylurea compounds and processes of their preparation. The process for preparing Glipizide disclosed in this patent involves reacting 5-methyl pyrazine-2- carboxylic acid with ethyl chloroformate in the presence of triethylamine followed by reacting with p-(4-amino-ethyl) benzene sulphonamide to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine- carboxamide. The crude product is then purified by crystallization from ethanol- water. The purified N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine- carboxamide is further reacted with cyclohexyl isocyanate in the presence of base to obtain Glipizide. Another process disclosed in this patent involves reaction of methyl pyrazine carboxylic acid with thionyl chloride to form corresponding acid chloride followed by reacting the acid chloride with p-(4-amino-ethyl) benzene sulphonamide to obtain N (2-(4-(aminosulfonyl)phenyl) ethyl pyrazine carboxamide. This compound is then treated with cyclohexylisocyanate to obtain Glipizide. When the present inventors followed this process, they noted that the
process resulted into formation of a sticky mass due to formation of number of impurities during reaction steps. Therefore, both preparation and isolation of products using the above process was difficult.
Indian patent application 2742/MUM/2013 disclosed preparation of Glipizide comprising a) preparing ester of 5-methylpyrazine-2-carboxylic acid by reacting 5- methylpyrazine-2-carboxylic acid in presence of alcohol and thionyl chloride (SOCb) at temperature 25-40°C; b) reacting ester of 5-methylpyrazine-2- carboxylic acid with 4-(2-aminoethyl)-benzene sulphonamide at 60-80°C to get 5- methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide; c) reacting 5- methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide with cyclohexyl isocyanate in presence of potassium carbonate and mixture of organic solvents to prepare Glipizide. Further it is disclosed that Glipizide is purified using mixture of alcohol and halogenating solvent to get pure Glipizide.
Thus, the above processes involve use of hazardous reagents like thionyl chloride, ethyl chloroformate etc.
CN102993106 disclosed synthesis of Glipizide which comprised of following reaction scheme.
11 \
The process involved use of hazardous reagent like ethychloroformate and expensive reagents like 1-hydroxybenzotriazole (HOBt) and l-ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride.
The present invention provides a simple, consistent, high yielding and industrially viable process for preparation of Glipizide.
Object of invention
An object of the invention is to provide new process for preparation of highly pure Glipizide.
Another object of the invention is to provide a simple, economic, consistent process for preparation of highly pure Glipizide with easy work-up procedure.
Yet another object of the invention is to provide a commercially viable and industrially applicable process for preparation of highly pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%. Brief description of drawings
Figure 1: It represents HPLC chromatogram of Blank.
Figure 2: It represents HPLC chromatogram of Glipizide as obtained in Example 5. Figure 3: It represents HPLC chromatogram of pure Glipizide as obtained in Example 10. Summary of invention
In accordance with the above objectives, the present invention provides a simple, economic, consistent, industrially feasible process for the preparation of Glipizide. According to an aspect, the present invention provides a process for preparation of Glipizide in a high yield and high purity for pharmaceutical use.
According to another aspect, the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate optionally in a solvent to obtain Glipizide in high yield and high purity.
According to yet another aspect, the present invention provides a process for preparation of Glipizide comprising
a) reacting 4-(2-aminoethyl)benzene sulfonamide and di-tert-butyl dicarbonate in presence of solvent to obtain tert-butyl 4-sulfamoylphenethylcarbamate;
b) reacting tert-butyl 4-sulfamoylphenethyl carbamate with cyclohexyl isocyanate in presence of alkali carbonate and solvent to obtain tert-butyl 4-(N- (cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate;
c) treating tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethylcarbamate with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N-
(cyclohexylcarbamoyl)benzenesulfonamide;
d) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide with alkyl ester of 5-methyl pyrazine-2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate to obtain Glipizide.
According to one more aspect, the present invention provides a process for purification of Glipizide to obtain Glipizide in purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
Detailed Description of invention
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.
The present invention provides a process for preparation of Glipizide in a high yield and high purity.
The monograph of Glipizide in the United States Pharmacopoeia (USP) mentions specifications for the impurities found in Glipizide. These impurities are determined by liquid chromatography according to the protocol described in the USP. Identified impurities comprise the following impurities: Compound A namely [N-{2-[(4- aminosulfonyl)phenyl]ethyl}-5-methyl-pyrazinecarboxamide], Compound B namely [6-methyl-N-[2-(4-sulfamoyl phenyl) ethyl]pyrazine-2-carboxamide] and Compound C namely [l-cyclohexyl-3-[[4-[2-[[(6-methyl pyrazin-2-yl)carbonyl] amino]ethyl]phenyl] sulfonylurea] .
The levels of the impurities of Glipizide of the present invention as obtained in crude and pure forms are as provided below. Even in crude form, the purity is at least 90 % and preferably above 95%.
Table 1
Figures 2 and 3 represent chromatograms of crude and pure Glipizide prepared according to example 5 and example 10 respectively of the present application. The inventors of the present invention have successfully arrived at pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%. The total impurities are restricted at less than 1.5 %, preferably less than 1.0% and most preferably less than 0.5%. Thus, Glipizide prepared according to this process comply with both USP and ICH requirements.
According to an embodiment, the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of alkali metal alkoxide optionally in a solvent to obtain Glipizide in high yield.
The alkyl ester of 5-methyl pyrazine-2-carboxylic acid is methyl 5-methylpyrazine- 2-carboxylate.
The alkali metal alkoxide is selected from the group consisting of sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, or mixtures thereof. The solvent used is alcohol for example methanol, ethanol, isopropanol, propanol and n-butanol.
A first aspect of the present invention is represented by reaction Scheme 1 as below:
Scheme 1
The process represented in scheme 1 comprises treating 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide with alkyl ester of 5 -methyl pyrazine- 2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate preferably sodium methoxide. The mixture is stirred and heated at temperature 25-100°C. The reaction is monitored by TLC or HPLC. It takes around 30 mins to 5 hrs for completion. Optionally a second lot of alkyl ester of 5 -methyl pyrazine-2-carboxylic acid and sodium methoxide solution is added to the mixture for the completion of reaction. When two lots of alkyl ester of 5-methyl pyrazine- 2-carboxylic acid and sodium methoxide are used for reaction, ratio of first lot to second lot for sodium methoxide is from at least 10: 1, preferably at least 15: 1 and ratio of first lot to second lot for methyl ester is at least 5: 1. After completion of reaction, water is added to the reaction mass and the reaction mass was acidified using hydrochloric acid. The mass is stirred for 1-2 hr to obtain solid Glipizide. According to one embodiment, the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of sodium methoxide at temperature in the range of 25-100°C for the period of from 30 min to 5 hours to obtain Glipizide in high yield.
According to another embodiment, the present invention provides a process for preparation of Glipizide comprising heating a mixture of 4-(2-aminoethyl)-N-
(cyclohexylcarbamoyl)benzene sulfonamide and methyl 5-methylpyrazine-2- carboxylate in presence of sodium methoxide solution. Alternatively, powdered sodium methoxide in a solvent can be used. Preferably, the reaction temperature is 50-90°C and reaction time is around 1-2 hr.
Preferably, sodium methoxide is in the form of 25% sodium methoxide solution in methanol.
According to an embodiment, the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of alkali metal carbonate and suitable solvent to obtain Glipizide.
The alkali metal carbonate is selected from the group consisting of potassium carbonate (K2CO3), sodium carbonate (Na2C03), potassium bicarbonate (KHCO3) and sodium bicarbonate (NaHC03).
The solvent used is selected from the group consisting of toluene, acetonitrile, isopropanol, methanol, DMF or mixtures thereof.
The reaction is carried out at temperature in the range of 25-100°C.
The reaction is carried out for 4-40hrs.
Preferably, the reaction of 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine-2-carboxylic acid is carried out in presence of alkali metal carbonate for example potassium carbonate and solvent for example toluene. The reaction mixture was stirred at refluxed temperature and maintained for 15-20hrs. After completion of reaction the solvent is distilled off from the reaction mixture. The mass is cooled to ambient temperature and water is added to the mass. The pH of reaction mass was brought to below 2.0 using acid for example dilute hydrochloric acid to obtain solid of Glipizide. Glipizide so obtained is then purified to get pure Glipizide.
According to second aspect the present invention provides a process for preparation of Glipizide comprising the steps of
1) reacting methyl 5-methylpyrazine-2-carboxylic acid (8) with acid in presence of solvent to obtain methyl 5-methylpyrazine-2-carboxylate (9);
2) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulphonamide (7) with methyl 5-methylpyrazine-2-carboxylate ester (9) in presence of alkali metal alkoxide or alkali metal carbonate to obtain Glipizide ( 1 ) in high yield;
3) optionally purifying Glipizide.
The acid used in step 1) is sulphuric acid. The solvent used in step 1) is methanol.
The reaction of step 1) is carried at 40-60°C for a period of 1 to 5hrs. Methyl 5-methylpyrazine-2-carboxylate used in step 2) can also be prepared by processes reported in the art.
The alkali metal alkoxide used in step 2) is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, potassium methoxide and sodium methoxide. Preferably sodium methoxide is used. The alkali metal carbonate used in step 2) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
The reaction of step 2) is carried out at temperature in the range of 25-100°C optionally in a solvent.
Preferably when alkali metal alkoxide is used as base in step 2) the reaction is carried out for 30min to 5hr. Preferably when alkali metal carbonate is used as base in step 2) the reaction is carried out for 4 to 40 hours. The solvent used is selected from toluene, acetonitrile, isopropanol, methanol, DMF or mixtures thereof.
The second embodiment of the present invention is represented by reaction Scheme 2.
Scheme 2
The process as represented in scheme 2 comprises the following steps:
a) 5-methylpyrazine-2-carboxylic acid in solvent for example methanol is treated with sulphuric acid. The mixture is heated to 50-55°C for 2-3 hrs.
After completion of reaction the mass is cooled to 40-45°C and solvent is distilled out under vacuum to get solid. The solid is treated with a solvent and/or a mixture of solvent for example methylene dichloride (MDC) and water. The mixture is stirred for 20-30 min. The separated organic layer is washed with sodium bicarbonate, treated with activated charcoal at 25° to
35°C and filtered. The solvent is distilled out from the mixture and the mass is treated with another solvent for example cyclohexane at temperature range from 25 °C to 45 °C. The reaction mass is then cooled to 10°C to 15°C to obtain solid of methyl 5-methylpyrazine-2-carboxylate.
b) treating 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate as obtained in step a) in presence of alkali metal alkoxide for example sodium methoxide solution or alkali metal carbonate for example sodium carbonate or potassium carbonate. Optionally the reaction is carried out in presence of solvent. The reaction mixture is stirred and heated at temperature 80-90°C. After completion of reaction, water is added to the reaction mass and the reaction
mass is acidified using hydrochloric acid. The mass is stirred for 1-2 hr to obtain solid of Glipizide.
According to third aspect, the present invention provides a process for preparation of Glipizide comprising 1) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzenesul fonamide (7);
2) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (7) with methyl 5-methylpyrazine-2-carboxylate (9) in presence of alkali metal alkoxide to obtain Glipizide (1) in high yield;
3) optionally purifying Glipizide.
This aspect of the present invention is represented by below reaction Scheme.
(6) CO
Scheme 3
The process as represented in scheme 3 comprises:
a) reacting tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate with suitable acid for example hydrochloric acid in presence of solvent for example methanol. The mixture is heated at 50-70°C with stirring for 2-6 hours. After completion of reaction the solvent is distilled out and water is added to the reaction mass. The reaction mass is then
neutralized using alkali for example sodium hydroxide solution to obtain 4- (2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide.
b) treating 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide for example sodium methoxide solution or alkali metal carbonate for example sodium carbonate or potassium carbonate. Optionally the reaction is carried out in presence of solvent. The reaction mixture is stirred and heated at temperature 80-90°C. After completion of reaction, water is added to the reaction mass and the reaction mass is acidified using hydrochloric acid. The mass is stirred for 1-2 hr to obtain solid of Glipizide. c) optionally purifying Glipizide.
Methyl 5-methylpyrazine-2-carboxylate as used in step b) is prepared by the procedures described in one or more embodiment of the present invention or it can be prepared by the processes reported in the art.
According to fourth aspect, the present invention provides a process for preparation of Glipizide comprising
1) reacting tert-butyl 4-sulfamoylphenethylcarbamate (4) with cyclohexylisocyanate (5) in presence of metal carbonate selected from sodium carbonate, cesium carbonate, potassium carbonate and solvent selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone to obtain tert-butyl 4-(N- (cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate (6);
2) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide (7);
3) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (7) with methyl 5-methylpyrazine-2-carboxylate (9) in presence of alkali metal alkoxide to obtain Glipizide (1) in high yield;
4) optionally purifying Glipizide.
This aspect of the present invention is represented by below reaction Scheme 4.
(?)
Scheme 4
The process as represented in scheme 4 comprises the steps of a) treating tert-butyl 4-sulfamoylphenethylcarbamate with potassium carbonate in presence of solvent for example acetone. The reaction mixture is heated to 50-55°C and cyclohexylisocyanate is added to it. The mixture is stirred for 2-6hr. The reaction mass is filtered and washed with solvent for example acetone or water or their mixture. The filtrate is acidified using acid for example hydrochloric acid to give solid of tert-butyl 4-(N-
(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate,
b) tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate obtained in step a) dissolved in solvent for example methanol and the solution is treated with acid for example hydrochloric acid at 50-55°C. After removing solvent from the mixture, the mass is treated with alkali for
example sodium hydroxide to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide or tert-butyl 4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate is deprotected by methods known in the prior art;
c) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide as obtained in step b) with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide for example sodium methoxide to obtain Glipizide;
d) optionally purifying Glipizide.
According to fifth aspect, the present invention provides a process for preparation of Glipizide comprising
1) reacting 4-(2-aminoethyl)benzenesulfonamide (2) and di-tert-butyl dicarbonate (3) in presence of solvent selected from the group consisting of dimethylacetamide, dimethylsulfoxide, N-methylpyrollidone and sulfolane to obtain tert-butyl 4-sulfamoylphenethylcarbamate (4);
2) reacting tert-butyl 4-sulfamoylphenethylcarbamate (4) with cyclohexylisocyanate (5) in presence of potassium carbonate and solvent to obtain tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate (6);
3) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with hydrochloric acid followed by alkaline treatment with sodium hydroxide to obtain 4-(2- aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulphonamide (7);
4) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (7) with methyl 5-methylpyrazine-2-carboxylate (9) in presence of sodium methoxide to obtain Glipizide (1) in high yield;
5) optionally purifying Glipizide.
This aspect of the present invention is represented by below reaction Scheme 5.
<5)
Scheme 5
The process as represented in scheme 5 comprises the steps of a) treating 4-(2-aminoethyl)benzenesulfonamide with di-tert-butyl dicarbonate in presence of solvent for example dimethylformamide for 2- 6hr at ambient temperature. After completion of reaction, water is added to the reaction mass and stirred the mixture for lhr to obtain solid of tert-butyl 4-sulfamoylphenethylcarbamate;
b) treating tert-butyl 4-sulfamoylphenethylcarbamate with potassium carbonate in presence of solvent for example acetone. The reaction mixture is heated to 50-55°C and cyclohexylisocyanate is added to it. The mixture
is stirred for 2-4 hr. The reaction mass is filtered and washed with solvent for example acetone. The pH of the filtrate is adjusted between 5 to 6 using acid for example hydrochloric acid to give tert-butyl 4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate;
c) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl) phenethyl carbamate in solvent is treated with acid for example hydrochloric acid at 50-55°C. After removing solvent from the mixture, the mass is treated with alkali for example sodium hydroxide to obtain 4-(2- aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulphonamide and d) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide as obtained in step c) with methyl 5-methylpyrazine-2-carboxylate ester in presence of alkali metal alkoxide for example sodium methoxide to obtain Glipizide.
e) optionally purifying Glipizide.
According to sixth aspect, the present invention provides a process for preparation of Glipizide comprising i) reacting 4-(2-aminoethyl)benzenesulfonamide (2) and di-tert-butyl decarbonate (3) in presence of solvent to obtain tert-butyl 4- sulfamoylphenethylcarbamate (4);
ii) reacting tert-butyl 4-sulfamoylphenethylcarbamate (4) with cyclohexylisocyanate (5) in presence of alkali carbonate and solvent to obtain tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate (6);
iii) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide (7);
iv) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (7) with methyl 5-methylpyrazine-2-carboxylate (9) in presence of alkali metal alkoxide to obtain Glipizide (1) in high yield; and
v) optionally purifying Glipizide.
According to seventh aspect, the present invention provides a process for purification of Glipizide to obtain Glipizide in high purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
The process for purification of Glipizide according to present invention comprising the steps of a) dissolving Glipizide in first solvent
b) heating the solution
c) optionally treating the solution of step b) with charcoal and filtering the solution
d) adding second solvent to the solution and
e) cooling the solution of step d) to obtain pure Glipizide.
The first solvent is selected from the group selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide and N-methylpyrrolidone.
The heating is carried out at 50-100°C.
The second solvent is alcohol selected from methanol, ethanol, isopropanol, propanol, n-butanol and water, or mixtures thereof.
In an embodiment, the process of purification of Glipizide involves, dissolving crude Glipizide in first solvent for example dimethylformamide to get a solution.
The solution is heated at 50-70°C and stirred for 10 min. The mixture is treated with activated charcoal and filtered the solution. Second solvent for example methanol. ethanol, isopropanol, n-butanol, preferably methanol is added to the filtrate at 50-
70°C and the mixture is stirred for 1-2 hr at the same temperature. The precipitate obtained is filtered, washed with solvent and dried to afford pure Glipizide.
According to another embodiment the process for purification of Glipizide comprises
a) dissolving Glipizide in dimethylformamide
b) heating the solution at 50° to 70°C
c) treating the solution of step b) with charcoal and filtering the solution d) adding methanol to the solution
e) cooling the solution of step d) to obtain pure Glipizide.
Glipizide obtained according to the present invention is having purity more than 99%.
In another embodiment, a process for preparing highly pure Glipizide comprising the steps of a) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide to obtain Glipizide; b) purifying Glipizide by heating a solution of Glipizide in dimethylformamide at 50° to 90°C, treating the solution with charcoal and filtering the solution, adding methanol to the solution and cooling the solution to obtain pure Glipizide having high purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.
The advantages of the process of present invention are
1. All the reagents used in the present invention are readily and commercially available and inexpensive, thus the present process is economical.
2. The present process is suitable for scale up production of Glipizide as it involves easy work up procedure and the reaction steps.
3. The present process avoids the use of hazardous reagents like thionyl chloride, ethyl chloroformate.
4. The present process avoids reaction conditions like reactions at low temperature for example below 0°C and high temperature which saves energy.
5. The present process avoids use of expensive coupling reagents like 1- hydroxybenzotriazole, Ν,Ν'-dicyclohexylcarbodimide, 1 -ethyl - (3- dimethylaminopropyl) carbodiimide hydrochloride (EDC HC1).
6. The present process is simple and consistent to achieve Glipizide in high yield and high purity.
The following examples are presented for illustrative purpose and not intended to limit the scope of this invention.
Examples
Example 1
Preparation of tert-butyl 4-sulfamoylphenethylcarbamate from 4-(2- aminoethyl)benzenesulfonamide
In a reaction vessel 4-(2-aminoethyl)benzenesulfonamide (50g, 0.24moles) was dissolved in dimethylformamide (200ml) at ambient temperature. Di-tert-butyl dicarbonate (54.5g, 0.24moles) was added slowly to the solution. The reaction mixture was stirred for 4 hr at ambient temperature. After completion of reaction water (600ml) was added to the reaction mass and stirred the mixture for 1 hr. The solid obtained was filtered, washed with water and dried to afford tert-butyl 4- sulfamoylphenethylcarbamate (73g). Yield: 97%
Example 2
Preparation of tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate
In a reaction vessel, tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (60g, 0.19moles), potassium carbonate (41.4g, 0.29moles) and acetone (250ml) were mixed. The mixture was heated to 50-55°C. Cyclohexylisocyanate (27.5g, 0.21moles) was added slowly to the mixture and the mass was stirred for 3hr at the same temperature. Again, a second lot of cyclohexylisocyanate (0.6moles) and potassium carbonate (0.9moles) was added to the reaction mixture. After completion of reaction, the mixture was cooled to room temperature, water (300 ml) was added and the mass was stirred for 30 min. The mixture was filtered. The undissolved salt was treated with acetone (20ml) and potassium carbonate solution (2.5% solution) in water (60ml) and filtered. The filtrates were combined in a reaction vessel and pH of the mixture was adjusted between 5 to 6 using diluted hydrochloric acid. The mixture was stirred for 1 hr. Solid obtained was filtered, washed with water (2x50ml) and dried to give tert-butyl 4- sulfamoylphenethylcarbamate (84g). Yield: 95%
Example 3
Preparation of 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide In a reaction vessel tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate (75g, 0.17moles) and methanol (525ml) were charged. Hydrochloric acid (37.5g, 0.34moles) was added slowly to the mixture and the mixture was heated to 50-55°C with stirring for 3hr. After completion of reaction methanol was distilled off under vacuum. The reaction mass was cooled 25°C to 35°C and water (225 ml) was added to the mass. The reaction mass was treated with sodium hydroxide solution (10% solution in water) to adjust the pH between 7 to 7.5. The mass was stirred for 30 min, solid obtained was filtered, washed with water (50ml) and dried to afford 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide (52.5g). Yield: 93.4%
Example 4
Preparation of Methyl 5-methylpyrazine-2-carboxylate
In a reaction vessel 5-methylpyrazine-2-carboxylic acid (25g, 0.18moles) was dissolved in methanol (250ml). Sulfuric acid (17.74g, 0.18moles) was added at ambient temperature and the mixture was heated to 55°C. The mixture was stirred for 4 hr. After completion of reaction methanol was distilled off under vacuum and charged dichloromethane (250ml) and water (150ml) to the reaction mass. The separated aqueous layer was extracted by dichloromethane (150ml) and then discarded. The combined organic layer was washed with 8% solution of sodium bicarbonate solution (2x125ml) and treated with sodium sulfate. Then activated charcoal (5g) was added to the solution and the mixture was stirred for 30 min. The reaction mass was filtered, washed with dichloromethane (100ml). The organic filtrate was heated to 35°C to 40°C and solvent was distilled out under vacuum. The mass obtained was charged with cyclohexane (100ml) and stir the mass for 5 to 10 min. The solvent was distilled out under vacuum. Again, the mass was charged with cyclohexane (200ml) and the mixture was cooled at 10° to 15°C followed by stirring for 60min. The solid obtained was filtered, washed with cyclohexane (50ml) and dried to afford methyl 5-methylpyrazine-2-carboxylate (22.7g). Yield: 82.7%
Example 5
Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide
4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (25g, 0.076 moles) and methyl 5-methylpyrazine-2-carboxylate (12.27g, 0.08moles) were charged and mixed in a reaction vessel. Solution of sodium methoxide in methanol (33.17g, 0.15moles) was added to the vessel. The mixture was stirred at 85°C for lhr and second lot of methyl 5-methylpyrazine-2-carboxylate (1.17g, 0.007moles) and 25% sodium methoxide solution (1.7g, 0.007moles) was added to the mass. After completion of reaction, the reaction mixture was cooled to 25°C to 35°C and water (125ml) was added to it. The mixture was acidified using diluted hydrochloric acid to precipitate out the solid. The solid obtained was filtered, washed with water (2x25ml) and dried to afford Glipizide (29g).
Yield: 84% Purity: 96.89% Example 6
Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide
4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (5g, 0.015 moles) and methyl 5-methylpyrazine-2-carboxylate (12.27g, 0.017moles) were charged and mixed in a reaction vessel. Solution of sodium methoxide in methanol (4.14g, 0.019 moles) was added to the vessel. The mixture was stirred at 120°C for lhr and second lot of methyl 5-methylpyrazine-2-carboxylate (0.46 g, 0.003 moles) and 25% sodium methoxide solution (0.66 g, 0.003 moles) was added to the mass. After completion of reaction, the reaction mixture was cooled to 25 °C to 35°C and water (25ml) was added to it. The mixture was acidified using diluted hydrochloric acid to precipitate out the solid. The solid obtained was filtered, washed with water (10ml) and dried to afford Glipizide (5.6g).
Yield: 81%
Example 7
Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide
In a reaction vessel, 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl) benzene sulfonamide (5g, 0.015moles), methyl 5-methylpyrazine-2-carboxylate (2.33g, 0.015moles) and methanol (10ml) were mixed. Potassium carbonate (4.22g, 0.03moles) and toluene (15ml) were added to the reaction mass and the mixture was stirred. Slowly temperature of the reaction mass was raised to 55°C to 60°C and maintained for 15hrs. After completion of reaction, the solvent was distilled off. The reaction mass was cooled to ambient temperature and water (20ml) was added to it. The pH of reaction mass was brought to below 2.0 using diluted hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford Glipizide (4.2g). Yield: 61%
Example 8
Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide
4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (lOg, 0.03moles), methyl 5-methylpyrazine-2-carboxylate (5.8g, O.038moles), sodium carbonate (5.4g, 0.051moles) and methanol (70ml) were mixed in a reaction vessel. Slowly temperature of reaction mass was raised to 55°C to 60°C and maintained for 40 hrs. After completion of reaction, solvent was distilled off from the reaction mixture. The reaction mass was cooled to ambient temperature and water (60 ml) was added to the reaction mass. The pH of reaction mass was brought to below 2.0 using diluted hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford solid of Glipizide (10.7g).
Yield: 78%
Example 9
Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide
4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (5g, 0.015 moles), methyl 5-methylpyrazine-2-carboxylate (2.6g, 0.017moles), powder sodium methoxide (4.15g, 0.019moles) and methanol (50ml) were mixed in a reaction vessel. Slowly temperature of reaction mass was raised to 55°C to 60°C and maintained for 26hrs. A second lot of powder sodium methoxide (0.67g, 0.003moles) was charged to the reaction mixture and maintained at 55°C to 60°C for 3hrs. After completion of reaction solvent was distilled off from the reaction mixture. The reaction mass was cooled to ambient temperature and water (20ml) was added to the mass. The pH of reaction mass was brought to below 2.0 using diluted hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford Glipizide (4.6g). Yield: 67%
Example 10
Purification of Glipizide
Glipizide (55 g) was dissolved in dimethylformamide (250ml). The solution was heated at 55°C and stirred for lOmin. The mixture was treated with activated charcoal (2.75g) and filtered the solution. Methanol (660ml) was added to the filtrate at 55°C and the mixture was stirred for 1 hr at the same temperature. The precipitate obtained was filtered, washed with methanol (50ml) and unloaded.
Further wet cake was treated with methanol (330ml) and heated the mixture at 60 to 65°C. The mixture was stirred for 30 min and cooled to ambient temperature.
The solid was filtered, washed with methanol (70ml) and dried to afford pure
Glipizide (32.5g).
Yield: 59%, Purity: 99.67%
Claims
A process for preparation of N-{4-[2-(5-methylpyrazinyl-2-carboxamido)- ethyl] -benzenesulphonyl } -N'-cyclohexylurea (Glipizide) comprising reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine-2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate to obtain Glipizide.
The process as claimed in claim 1 wherein said alkyl ester of methyl pyrazine-2-carboxylic acid is methyl 5-methylpyrazine-2-carboxylate. The process as claimed in claim 1 wherein said alkali metal alkoxide is selected from group consisting of sodium tert-butoxide, potassium tert- butoxide, potassium methoxide and sodium methoxide.
The process as claimed in claim 1 wherein said alkali metal carbonate is selected from group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, lithium carbonate and lithium bicarbonate.
The process as claimed in claim 1 wherein said reaction is carried out in presence of base, alkali metal alkoxide optionally in a solvent at temperature in the range of 25-100°C for a period of 30 min to 3 hours.
The process as claimed in claim 1 wherein said reaction is carried out in presence of base, alkali metal carbonate and solvent at temperature in the range of 25-100°C for a period of 4 to 40 hours.
The process as claimed in claim 5 and 6 wherein said solvent is selected from toluene, acetonitrile, isopropanol, methanol, dimethylformamide or mixtures thereof.
A process for preparation of Glipizide comprising
i) reacting 4-(2-aminoethyl)benzenesulfonamide and di-tert-butyl dicarbonate in presence of solvent to obtain tert-butyl 4- sulfamoylphenethylcarbamate;
ii) reacting tert-butyl 4-sulfamoylphenethylcarbamate with cyclohexylisocyanate in presence of alkali carbonate and solvent to obtain tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate; iii) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide;
iv) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide to obtain Glipizide in high yield; and
v) optionally purifying Glipizide.
9. The process as claimed in any of the preceding claims wherein said alkali metal alkoxide is selected from group consisting of sodium tert-butoxide, potassium tert-butoxide, potassium methoxide, sodium methoxide
10. A purification of Glipizide comprising
a) dissolving Glipizide in first solvent
b) heating the solution
c) optionally treating the solution of step b) with charcoal and filtering the solution
d) adding second solvent to the solution
e) cooling the solution of step d) to obtain pure Glipizide.
11. The process as claimed in claim 10 wherein said first solvent is selected from the group consisting of dimethylformamide, dimethylsulfoxide, dimethylacetamide and N-methylpyrrolidone.
12. The process as claimed in claim 10 wherein said second solvent is alcohol selected from methanol, ethanol, isopropanol, propanol, n-butanol and water, or mixtures thereof.
13. The process as claimed in claim 10 wherein said heating in step b) and adding second solvent in step d) is carried out at 50-100°C to obtain a solution.
14. A process for preparing Glipizide having purity more than 99% comprising the steps of a) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide to obtain Glipizide; b) purifying Glipizide by heating a solution of Glipizide in dimethylformamide at 50° to 90°C, treating the solution with charcoal and filtering the solution, adding methanol to the solution and cooling the solution to obtain pure Glipizide.
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Citations (1)
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| US3669966A (en) * | 1969-03-26 | 1972-06-13 | Erba Carlo Spa | Pyrazine derivatives and process for their preparation |
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