HUP0302688A2 - Eljárások cilostazol előállítására - Google Patents

Eljárások cilostazol előállítására Download PDF

Info

Publication number: HUP0302688A2
Authority: HU; Hungary
Prior art keywords: tetrazole; cilostazol; cyclohexyl; alkali metal; dihydroquinolinone
Prior art date: 2000-08-14

Application number

HU0302688A

Other languages

English (en)

Hungarian (hu)

Inventor

Nina Finkelstein

Marioara Mendelovichi

Gideon Pilarksi

Original Assignee

Teva Pharmaceutical Industries, Ltd.

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2000-08-14

Filing date

2001-08-14

Publication date

2003-12-29

2001-08-14 Application filed by Teva Pharmaceutical Industries, Ltd. filed Critical Teva Pharmaceutical Industries, Ltd.

2003-12-29 Publication of HUP0302688A2 publication Critical patent/HUP0302688A2/hu

Links

238000000034 method Methods 0.000 title claims abstract description 56
RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 title claims abstract description 54
229960004588 cilostazol Drugs 0.000 title claims abstract description 53
230000008569 process Effects 0.000 title claims abstract description 37
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 48
150000003536 tetrazoles Chemical class 0.000 claims description 43
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 32
239000000243 solution Substances 0.000 claims description 27
239000000203 mixture Substances 0.000 claims description 26
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 23
238000006243 chemical reaction Methods 0.000 claims description 23
239000002904 solvent Substances 0.000 claims description 22
150000008044 alkali metal hydroxides Chemical class 0.000 claims description 18
239000002585 base Substances 0.000 claims description 18
235000011118 potassium hydroxide Nutrition 0.000 claims description 16
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
239000003444 phase transfer catalyst Substances 0.000 claims description 15
238000002360 preparation method Methods 0.000 claims description 15
239000012071 phase Substances 0.000 claims description 14
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
239000002808 molecular sieve Substances 0.000 claims description 12
239000011541 reaction mixture Substances 0.000 claims description 12
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 12
HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical compound N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 claims description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 8
150000008041 alkali metal carbonates Chemical class 0.000 claims description 8
BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 8
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 8
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
239000007864 aqueous solution Substances 0.000 claims description 7
229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
235000011121 sodium hydroxide Nutrition 0.000 claims description 7
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
239000003513 alkali Substances 0.000 claims description 5
239000008346 aqueous phase Substances 0.000 claims description 5
HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 5
XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 5
229940031826 phenolate Drugs 0.000 claims description 5
235000011181 potassium carbonates Nutrition 0.000 claims description 5
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
INTQSGGUSUSCTJ-UHFFFAOYSA-N 5-(4-chlorobutyl)-1-cyclohexyltetrazole Chemical group ClCCCCC1=NN=NN1C1CCCCC1 INTQSGGUSUSCTJ-UHFFFAOYSA-N 0.000 claims description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
239000006227 byproduct Substances 0.000 claims description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
239000002245 particle Substances 0.000 claims description 4
ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims description 4
229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
235000011152 sodium sulphate Nutrition 0.000 claims description 4
239000000126 substance Substances 0.000 claims description 4
ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 3
CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 3
GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 3
FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 3
OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 3
239000012074 organic phase Substances 0.000 claims description 3
HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 3
229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 2
OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 2
AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
UDYGXWPMSJPFDG-UHFFFAOYSA-M benzyl(tributyl)azanium;bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 UDYGXWPMSJPFDG-UHFFFAOYSA-M 0.000 claims description 2
DVBJBNKEBPCGSY-UHFFFAOYSA-M cetylpyridinium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 DVBJBNKEBPCGSY-UHFFFAOYSA-M 0.000 claims description 2
WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims description 2
238000009826 distribution Methods 0.000 claims description 2
239000000463 material Substances 0.000 claims description 2
RAYLUPYCGGKXQO-UHFFFAOYSA-N n,n-dimethylacetamide;hydrate Chemical compound O.CN(C)C(C)=O RAYLUPYCGGKXQO-UHFFFAOYSA-N 0.000 claims description 2
WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
235000015320 potassium carbonate Nutrition 0.000 claims description 2
238000001953 recrystallisation Methods 0.000 claims description 2
235000017550 sodium carbonate Nutrition 0.000 claims description 2
NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 2
VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 2
DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 2
WPPGURUIRLDHAB-UHFFFAOYSA-M triethyl(hexadecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](CC)(CC)CC WPPGURUIRLDHAB-UHFFFAOYSA-M 0.000 claims description 2
AQZSPJRLCJSOED-UHFFFAOYSA-M trimethyl(octyl)azanium;chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(C)C AQZSPJRLCJSOED-UHFFFAOYSA-M 0.000 claims description 2
125000001453 quaternary ammonium group Chemical group 0.000 claims 4
TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 claims 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
239000003125 aqueous solvent Substances 0.000 claims 2
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
230000003213 activating effect Effects 0.000 claims 1
230000004913 activation Effects 0.000 claims 1
150000003278 haem Chemical class 0.000 claims 1
229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
235000017557 sodium bicarbonate Nutrition 0.000 claims 1
238000004519 manufacturing process Methods 0.000 abstract description 6
206010022562 Intermittent claudication Diseases 0.000 abstract description 2
208000021156 intermittent vascular claudication Diseases 0.000 abstract description 2
208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 2
238000010992 reflux Methods 0.000 description 23
150000007529 inorganic bases Chemical class 0.000 description 9
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
239000003960 organic solvent Substances 0.000 description 6
230000002152 alkylating effect Effects 0.000 description 5
238000001816 cooling Methods 0.000 description 5
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
230000006872 improvement Effects 0.000 description 4
150000007530 organic bases Chemical class 0.000 description 4
239000000047 product Substances 0.000 description 4
239000002002 slurry Substances 0.000 description 4
239000007787 solid Substances 0.000 description 4
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
229910052783 alkali metal Inorganic materials 0.000 description 3
150000001340 alkali metals Chemical class 0.000 description 3
238000005804 alkylation reaction Methods 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
239000007788 liquid Substances 0.000 description 3
239000011734 sodium Substances 0.000 description 3
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
238000000944 Soxhlet extraction Methods 0.000 description 2
230000029936 alkylation Effects 0.000 description 2
230000008901 benefit Effects 0.000 description 2
229910052799 carbon Inorganic materials 0.000 description 2
150000001721 carbon Chemical group 0.000 description 2
229910052801 chlorine Inorganic materials 0.000 description 2
239000000460 chlorine Substances 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
239000012043 crude product Substances 0.000 description 2
229910052736 halogen Inorganic materials 0.000 description 2
150000002367 halogens Chemical class 0.000 description 2
229910052700 potassium Inorganic materials 0.000 description 2
239000011591 potassium Substances 0.000 description 2
150000003839 salts Chemical class 0.000 description 2
239000007858 starting material Substances 0.000 description 2
238000006467 substitution reaction Methods 0.000 description 2
230000009466 transformation Effects 0.000 description 2
ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
150000003863 ammonium salts Chemical class 0.000 description 1
239000012736 aqueous medium Substances 0.000 description 1
239000007900 aqueous suspension Substances 0.000 description 1
235000019445 benzyl alcohol Nutrition 0.000 description 1
230000002051 biphasic effect Effects 0.000 description 1
239000012455 biphasic mixture Substances 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
230000003139 buffering effect Effects 0.000 description 1
244000309464 bull Species 0.000 description 1
125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
150000004649 carbonic acid derivatives Chemical class 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
238000004140 cleaning Methods 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
239000013078 crystal Substances 0.000 description 1
238000006731 degradation reaction Methods 0.000 description 1
239000012024 dehydrating agents‎ Substances 0.000 description 1
230000018044 dehydration Effects 0.000 description 1
238000006297 dehydration reaction Methods 0.000 description 1
238000010511 deprotection reaction Methods 0.000 description 1
SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
239000000539 dimer Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
-1 for example Substances 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
150000004679 hydroxides Chemical class 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
150000003951 lactams Chemical class 0.000 description 1
238000011031 large-scale manufacturing process Methods 0.000 description 1
231100001231 less toxic Toxicity 0.000 description 1
239000012035 limiting reagent Substances 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
229910052757 nitrogen Inorganic materials 0.000 description 1
230000000269 nucleophilic effect Effects 0.000 description 1
239000011368 organic material Substances 0.000 description 1
239000003791 organic solvent mixture Substances 0.000 description 1
210000002741 palatine tonsil Anatomy 0.000 description 1
238000003408 phase transfer catalysis Methods 0.000 description 1
239000011736 potassium bicarbonate Substances 0.000 description 1
235000015497 potassium bicarbonate Nutrition 0.000 description 1
229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
229910052939 potassium sulfate Inorganic materials 0.000 description 1
235000011151 potassium sulphates Nutrition 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
150000003242 quaternary ammonium salts Chemical class 0.000 description 1
239000002994 raw material Substances 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
238000010956 selective crystallization Methods 0.000 description 1
229910001958 silver carbonate Inorganic materials 0.000 description 1
LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
239000007790 solid phase Substances 0.000 description 1
125000005207 tetraalkylammonium group Chemical group 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
230000007704 transition Effects 0.000 description 1
IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
239000008096 xylene Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Life Sciences & Earth Sciences (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Hematology (AREA)
Diabetes (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Plural Heterocyclic Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Cephalosporin Compounds (AREA)
Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

HU0302688A 2000-08-14 2001-08-14 Eljárások cilostazol előállítására HUP0302688A2 (hu)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US22536200P	2000-08-14	2000-08-14
PCT/US2001/025398 WO2002014283A1 (en)	2000-08-14	2001-08-14	Processes for preparing cilostazol

Publications (1)

Publication Number	Publication Date
HUP0302688A2 true HUP0302688A2 (hu)	2003-12-29

Family

ID=22844569

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HU0302688A HUP0302688A2 (hu)	2000-08-14	2001-08-14	Eljárások cilostazol előállítására

Country Status (17)

Country	Link
EP (1)	EP1311485A4 (pl)
JP (2)	JP3845059B2 (pl)
KR (1)	KR20030024865A (pl)
CN (1)	CN1469864A (pl)
AU (1)	AU2001284887A1 (pl)
CA (1)	CA2419181A1 (pl)
CZ (1)	CZ2003667A3 (pl)
HK (1)	HK1053116A1 (pl)
HU (1)	HUP0302688A2 (pl)
IL (1)	IL154458A0 (pl)
IS (1)	IS6716A (pl)
MX (1)	MXPA03001470A (pl)
NO (1)	NO20030699L (pl)
NZ (1)	NZ524363A (pl)
PL (1)	PL365672A1 (pl)
SK (1)	SK2992003A3 (pl)
WO (1)	WO2002014283A1 (pl)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US20030045547A1 (en)	2001-05-02	2003-03-06	Shinji Aki	Process for producing carbostyril derivatives
US20050101631A1 (en)	2002-08-01	2005-05-12	Otsuka Pharmaceuticals Company	Process for producing carbostyril derivatives
US7399864B2 (en)	2001-05-02	2008-07-15	Otsuka Pharmaceutical Co., Ltd.	Process for producing carbostyril derivatives
EP1489080B1 (en)	2002-09-10	2011-01-26	Otsuka Pharmaceutical Co., Ltd.	Process for producing cilostazol
DE202005020551U1 (de) *	2004-02-05	2006-07-06	Teva Pharmaceutical Industries Ltd.	7-(4-Brombutoxy)-3,4-dihydrocarbostyril
KR100633232B1 (ko) *	2004-08-25	2006-10-11	주식회사유한양행	신규한 6-[4-(1-시클로헥실-1ｈ-테트라졸-5-일)부톡시]-3,4-디히드로-2(1ｈ)-퀴놀리논 정제방법
JP2008543953A (ja) *	2006-04-20	2008-12-04	テバファーマシューティカルインダストリーズリミティド	エスゾピクロン結晶形態ａ、実質的に純粋なエスゾピクロン及び光学的に豊富なエスゾピクロンを調製するための方法
TW200848041A (en)	2007-03-30	2008-12-16	Otsuka Pharma Co Ltd	A medicament for treating schizophrenia comprising cilostazol
ES2401914T3 (es)	2007-04-25	2013-04-25	Concert Pharmaceuticals Inc.	Análogos de Cilostazol
CN101434598B (zh) *	2008-12-19	2012-11-07	重庆康乐制药有限公司	西洛他唑的制备方法
CN102086190B (zh) *	2011-01-28	2013-07-10	海南美兰史克制药有限公司	西洛他唑化合物及其制法
CN107382970A (zh) *	2017-07-26	2017-11-24	浙江金立源药业有限公司	一种西洛他唑的合成方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JPS5535019A (en) *	1978-09-01	1980-03-11	Otsuka Pharmaceut Co Ltd	Carbostyryl derivative
JPH01265051A (ja) *	1988-04-14	1989-10-23	Fuji Photo Film Co Ltd	ジアリールオキシアルカン製造方法

2001
- 2001-08-14 CZ CZ2003667A patent/CZ2003667A3/cs unknown
- 2001-08-14 CA CA002419181A patent/CA2419181A1/en not_active Abandoned
- 2001-08-14 AU AU2001284887A patent/AU2001284887A1/en not_active Abandoned
- 2001-08-14 WO PCT/US2001/025398 patent/WO2002014283A1/en not_active Ceased
- 2001-08-14 MX MXPA03001470A patent/MXPA03001470A/es unknown
- 2001-08-14 SK SK299-2003A patent/SK2992003A3/sk unknown
- 2001-08-14 KR KR10-2003-7002140A patent/KR20030024865A/ko not_active Ceased
- 2001-08-14 JP JP2002519426A patent/JP3845059B2/ja not_active Expired - Fee Related
- 2001-08-14 EP EP01963979A patent/EP1311485A4/en not_active Withdrawn
- 2001-08-14 IL IL15445801A patent/IL154458A0/xx unknown
- 2001-08-14 HU HU0302688A patent/HUP0302688A2/hu unknown
- 2001-08-14 PL PL01365672A patent/PL365672A1/pl unknown
- 2001-08-14 NZ NZ524363A patent/NZ524363A/en unknown
- 2001-08-14 HK HK03105399.3A patent/HK1053116A1/zh unknown
- 2001-08-14 CN CNA018172083A patent/CN1469864A/zh active Pending
2003
- 2003-02-13 IS IS6716A patent/IS6716A/is unknown
- 2003-02-13 NO NO20030699A patent/NO20030699L/no not_active Application Discontinuation
2005
- 2005-06-21 JP JP2005181031A patent/JP2005350474A/ja active Pending

Also Published As

Publication number	Publication date
JP2004506043A (ja)	2004-02-26
NZ524363A (en)	2004-03-26
EP1311485A1 (en)	2003-05-21
KR20030024865A (ko)	2003-03-26
CN1469864A (zh)	2004-01-21
NO20030699L (no)	2003-04-10
NO20030699D0 (no)	2003-02-13
CA2419181A1 (en)	2002-02-21
SK2992003A3 (en)	2003-10-07
WO2002014283A1 (en)	2002-02-21
HK1053116A1 (zh)	2003-10-10
JP3845059B2 (ja)	2006-11-15
AU2001284887A1 (en)	2002-02-25
IS6716A (is)	2003-02-13
MXPA03001470A (es)	2005-06-30
PL365672A1 (pl)	2005-01-10
JP2005350474A (ja)	2005-12-22
EP1311485A4 (en)	2004-05-12
CZ2003667A3 (cs)	2003-08-13
IL154458A0 (en)	2003-09-17

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