WO2010104344A2 - Process for preparing prostaglandin derivatives - Google Patents
Process for preparing prostaglandin derivatives Download PDFInfo
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- WO2010104344A2 WO2010104344A2 PCT/KR2010/001529 KR2010001529W WO2010104344A2 WO 2010104344 A2 WO2010104344 A2 WO 2010104344A2 KR 2010001529 W KR2010001529 W KR 2010001529W WO 2010104344 A2 WO2010104344 A2 WO 2010104344A2
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- process according
- derivative
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- following formula
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- 150000003180 prostaglandins Chemical class 0.000 title abstract description 9
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 claims abstract description 28
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims abstract description 26
- 125000006239 protecting group Chemical group 0.000 claims abstract description 14
- BGTOWKSIORTVQH-HOSYLAQJSA-N cyclopentanone Chemical group O=[13C]1CCCC1 BGTOWKSIORTVQH-HOSYLAQJSA-N 0.000 claims abstract description 8
- 125000000468 ketone group Chemical group 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 25
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- -1 triethylsilyl Chemical group 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 11
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 10
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229960002368 travoprost Drugs 0.000 claims description 8
- 229960002470 bimatoprost Drugs 0.000 claims description 7
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 229960001160 latanoprost Drugs 0.000 description 6
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 6
- 0 C[C@@]1(C(CC=CCCCC(**)=O)=C[C@@](*)C1)O Chemical compound C[C@@]1(C(CC=CCCCC(**)=O)=C[C@@](*)C1)O 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000007012 clinical effect Effects 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 210000000720 eyelash Anatomy 0.000 description 2
- 150000002222 fluorine compounds Chemical class 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- UQBYFURYGYNQLQ-FDBOBMRISA-N COC(CCC/C=C\C[C@@H]([C@H](C[C@H]1O)O)[C@H]1/C=C/[C@H](CCc1ccccc1)O)=O Chemical compound COC(CCC/C=C\C[C@@H]([C@H](C[C@H]1O)O)[C@H]1/C=C/[C@H](CCc1ccccc1)O)=O UQBYFURYGYNQLQ-FDBOBMRISA-N 0.000 description 1
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 1
- 229910003638 H2SiF6 Inorganic materials 0.000 description 1
- RGWKJPVSUDHANQ-VJZARVIVSA-N O[C@@H](COc1cc(C(F)(F)F)ccc1)/C=C/[C@H](CC(C1)=O)[C@@H]1O Chemical compound O[C@@H](COc1cc(C(F)(F)F)ccc1)/C=C/[C@H](CC(C1)=O)[C@@H]1O RGWKJPVSUDHANQ-VJZARVIVSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- ZEFWRWWINDLIIV-UHFFFAOYSA-N tetrafluorosilane;dihydrofluoride Chemical compound F.F.F[Si](F)(F)F ZEFWRWWINDLIIV-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/608—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
- C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a process for efficiently preparing a prostaglandin derivative with high purity and an intermediate therefor.
- Prostaglandin derivatives particularly travoprost, bimatoprost and latanoprost of the following formula (2) have been extensively used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth.
- the prostaglandin derivatives have been conventionally prepared through many synthetic steps in poor yields.
- the most common commercial processes use Corey lactone as a starting material to produce the prostaglandin derivatives, as shown in the following Reaction Scheme 1 ( see E.J. Corey et al., J. Amer. Chem. Soc., 91, 5675-5677, 1969).
- Corey lactone is expensive and the processes require a chromatographic separation for removing ⁇ -OH which is produced as a by-product on the reduction of 15-ketone group into ⁇ -OH after the introduction of ⁇ -chain. Therefore, the processes are unsuitable for large-scale production of the prostaglandin derivatives in terms of poor yields and high costs.
- the ⁇ -OH produced as a by-product may be reduced by using a chiral borane compound as a stereoselective reducing agent, but the chiral borane compound is also very expensive.
- PGF prostaglandin F
- PGE prostaglandin E
- the present inventors have endeavored to overcome the above problems and found that a highly pure PGF derivative having little or no ⁇ -OH can be efficiently prepared by removing the protecting group of the prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring.
- PGE prostaglandin E
- An object of the present invention is, therefore, to provide a process for efficiently preparing a PGF derivative with high purity.
- Another object of the present invention is to provide a novel intermediate used in said process.
- One aspect of the present invention relates to a process for preparing a prostaglandin F (PGF) derivative of the following formula (1), which comprises the steps of:
- X is O or NH
- Y is ⁇ -OH or difluoro, preferably ⁇ -OH;
- Y' is ⁇ -OPG or difluoro, preferably ⁇ -OPG;
- Z is CH 2 , O or S, preferably CH 2 or O;
- R is H or C 1 -C 5 alkyl, preferably C 1 -C 5 alkyl
- R' is C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl or aryl, preferably phenyl optionally substituted by C 1 -C 5 haloalkyl or halogen, more preferably CF 3 , Cl or F, most preferably CF 3 ;
- PG is a hydroxy protecting group, preferably tetrahydropyranyl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl, more preferably triethylsilyl.
- C 1 -C 5 alkyl as used herein means a straight or branched hydrocarbon having 1 to 5 carbon atoms, which includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, etc., but is not limited thereto.
- C 3 -C 7 cycloalkyl as used herein means a cyclic hydrocarbon having 3 to 7 carbon atoms, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but is not limited thereto.
- aryl as used herein includes all of aromatic group, heteroaromatic group and partially reduced derivatives thereof.
- the aromatic group means a 5 to 15-membered simple or fused ring.
- the heteroaromatic group means an aromatic group containing at least one atom selected from oxygen, sulfur and nitrogen. Examples of the aryl include phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, oxazolyl, thiazolyl, tetrahydronaphthyl, etc., but are not limited thereto.
- the C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl and aryl may have one or more hydrogens substituted by C 1 -C 5 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 5 haloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 thioalkoxy, aryl, acyl, hydroxy, thio, halogen, amino, alkoxycarbonyl, carboxyl, carbamoyl, cyano, nitro, etc.
- the prostaglandin E (PGE) derivative of formula (6) is prepared by removing the hydroxy protecting group of the protected PGE derivative of formula (5).
- the deprotection may be carried out under an acidic condition.
- silyl protecting groups may be deprotected by using various fluoride compounds.
- the acidic condition for silyl protecting groups may be provided by the use of d-HCl, an aqueous NaHSO 4 solution, pyridinium p-toluensulfonate (PPTS), etc.
- PPTS pyridinium p-toluensulfonate
- fluoride compounds include tetrabutylammonium fluoride (Bu 4 N + F - ), hydrogen fluoride-pyridine (HF-pyridine), fluorosilicic acid (H 2 SiF 6 ), etc., but are not limited thereto.
- the compound of formula (5) having a carbon-carbon double bond at 13 and 14 position may be prepared by converting an alkenyl tin compound of the following formula (3) to its cuprate, followed by conjugate addition to a cyclopentenone compound of the following formula (4), according to a known method ( see J. Am. Chem. Soc. 1988, 110, 2641-2643).
- the alkenyl tin compound of formula (3) is added to a solution of Me 2 Cu(CN)Li 2 and converted to a higher order mixed cuprate of the following formula (7), which is subjected to conjugate addition to the cyclopentenone compound of formula (4).
- the above reaction is preferably carried out in a mixture of tetrahydrofuran (THF) and hexane or a mixture of THF and ether, most preferably a mixture of THF and diethyl ether, as a solvent.
- THF tetrahydrofuran
- ether a mixture of THF and ether, most preferably a mixture of THF and diethyl ether, as a solvent.
- the conjugate addition is preferably carried out in a low temperature of -60 °C or less.
- the alkenyl tin compound of formula (3) may be prepared by reacting a ⁇ -chain precursor containing a terminal acetylene group with Bu 3 SnH, according to a known method ( see J. Am. Chem. Soc. 1988, 110, 2641-2643).
- the compound of formula (5) having a carbon-carbon single bond at 13 and 14 position may be prepared by the method disclosed in WO 02/090324.
- the prostaglandin F (PGF) derivative of formula (1) is prepared by stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of formula (6).
- a reducing agent used in the present invention includes sodium borohydride (NaBH 4 ), L-selectride, N-selectride, K-selectride, LS-selectride, 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL), etc., but is not limited thereto.
- NaBH 4 sodium borohydride
- L-selectride L-selectride
- N-selectride N-selectride
- K-selectride K-selectride
- LS-selectride 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL), etc.
- DIBAL diisobutyl aluminium hydride
- 2,6-di-tert-butyl-4-methyl phenol and DIBAL leads to stereoselective preparation of ⁇ -OH compound having no ⁇ -OH.
- the reduction is carried out by reacting 2,6-di-tert-butyl-4-methyl phenol in an amount of 2 to 10 equivalents, preferably 5 equivalents with DIBAL in an amount of 2 to 5 equivalents, preferably 4 equivalents in toluene as a solvent at -10 to 10 °C, preferably 0 °C for 1 to 2 hours, preferably 1 hour; lowering the temperature of the reaction solution to -70 °C; adding the compound of formula (6) thereto, followed by stirring for 1 to 3 hours, preferably 2 hours; raising the temperature of the reaction solution to -40 to -20 °C, preferably -30 °C; and stirring the reaction solution for 3 to 6 hours, preferably 4 hours.
- the prostaglandin F (PGF) derivative of formula (1) wherein X is NH may be prepared by reacting the PGF derivative of formula (1) wherein X is O and R is methyl, with RNH 2 .
- the above reaction is preferably carried out at room temperature.
- Examples of the prostaglandin F (PGF) derivative of formula (1) prepared by the present process include travoprost, bimatoprost and latanoprost, which are widely used due to their clinical effects such as reducing intraocular pressure and promoting hair and eyelash growth.
- travoprost, bimatoprost and latanoprost can be prepared with high purity of 99.5% or more by further comprising the step of purifying them by HPLC using a mixture of hydrocarbon and alcohol, preferably a mixture of n-hexane and anhydrous ethanol or a mixture of n-heptane and anhydrous ethanol, or a mixture of dichloromethane and alcohol, preferably a mixture of dichloromethane and isopropanol.
- Another aspect of the present invention relates to a compound of the following formula (8), which is an intermediate of travoprost, and a compound of formula (9), which is an intermediate of bimatoprost.
- the prostaglandin F (PGF) derivative can be efficiently prepared with high purity by removing the protecting group of the protected prostaglandin E (PGE) derivative obtained from conjugate addition and then stereoselectively reducing the ketone group on the cyclopentanone ring of the PGE derivative.
- the ⁇ -OH compound having no ⁇ -OH can be stereoselectively prepared using 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL) as a reducing agent.
- DIBAL diisobutyl aluminium hydride
- 2,6-Di-tert-butyl-4-methyl phenol (560 g) was dissolved in toluene (6.5 L), followed by cooling to 0 °C, and DIBAL (1.0 M toluene, 2.05 L) was added dropwise thereto for 1 hour.
- the resulting reaction solution was cooled to -70 °C, and compound (6-II) (205 g) dissolved in toluene (1.6 L) was added dropwise thereto.
- the resulting reaction solution was stirred for about 2 hours, and its temperature was slowly raised to -40 to -20 °C, followed by stirring for 4 hours. After the reaction was completed, an aqueous 2N hydrochloric acid solution (2.5 L) was added.
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Abstract
Description
Claims (20)
- A process for preparing a prostaglandin F (PGF) derivative of the following formula (1), which comprises the steps of:(i) removing the hydroxy protecting group of a protected prostaglandin E (PGE) derivative of the following formula (5) to give a prostaglandin E (PGE) derivative of the following formula (6); and(ii) stereoselectively reducing the ketone group on the cyclopentanone ring of the compound of the following formula (6):wherein,X is O or NH;Y is α-OH or difluoro;Y' is α-OPG or difluoro;Z is CH2, O or S;R is H or C1-C5 alkyl;R' is C1-C5 alkyl, C3-C7 cycloalkyl or aryl; andPG is a hydroxy protecting group.
- The process according to any one of claims 1 to 4, wherein the hydroxy protecting group is tetrahydropyranyl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl.
- The process according to claim 5, wherein the hydroxy protecting group is triethylsilyl.
- The process according to any one of claims 1 to 4, wherein the hydroxy protecting group of the protected PGE derivative of formula (5) is removed under an acidic condition in step (i).
- The process according to claim 7, wherein the acidic condition is provided by the use of pyridinium p-toluensulfonate (PPTS).
- The process according to any one of claims 1 to 4, wherein the protected PGE derivative of formula (5) in which is a double bond is prepared by converting an alkenyl tin compound of the following formula (3) to its cuprate, and subjecting the cuprate to conjugate addition to a cyclopentenone compound of the following formula (4):
- The process according to any one of claims 1 to 4, wherein the reduction in step (ii) is carried out by using a reducing agent selected from the group consisting of sodium borohydride (NaBH4), L-selectride, N-selectride, K-selectride, LS-selectride, and 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL).
- The process according to claim 11, wherein the reducing agent is 2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminium hydride (DIBAL).
- The process according to any one of claims 1 to 4, wherein the prostaglandin F (PGF) derivative of formula (1) in which X is NH is prepared by reacting the PGF derivative of formula (1) in which X is O and R is methyl, with RNH2.
- The process according to any one of claims 1 to 4, which further comprises the step of purifying the prostaglandin F (PGF) derivative of formula (1) by HPLC using a mixture of hydrocarbon and alcohol or a mixture of dichloromethane and alcohol.
- The process according to claim 14, wherein the mixture of hydrocarbon and alcohol is a mixture of n-hexane and anhydrous ethanol or a mixture of n-heptane and anhydrous ethanol.
- The process according to claim 14, wherein the mixture of dichloromethane and alcohol is a mixture of dichloromethane and isopropanol.
- Travoprost having a purity of 99.5% or more.
- Bimatoprost having a purity of 99.5% or more.
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JP2011553956A JP5490155B2 (en) | 2009-03-11 | 2010-03-11 | Method for producing prostaglandin derivative |
US13/255,417 US9126898B2 (en) | 2009-03-11 | 2010-03-11 | Process for preparing prostaglandin derivatives |
US13/901,170 US20130253218A1 (en) | 2009-03-11 | 2013-05-23 | Process for preparing prostaglandin derivatives |
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KR1020090020920A KR101045935B1 (en) | 2009-03-11 | 2009-03-11 | Method for preparing prostaglandin derivative |
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WO2013164729A1 (en) | 2012-05-03 | 2013-11-07 | Lupin Limited | An improved and scalable process for preparation of prostaglandin derivatives and intermediates thereof |
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CN104297352A (en) * | 2013-07-16 | 2015-01-21 | 天津金耀集团有限公司 | Method of analyzing travoprost content and related compounds |
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WO2015136317A1 (en) | 2014-03-13 | 2015-09-17 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | New process for the preparation of high purity prostaglandins |
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US20120108839A1 (en) | 2012-05-03 |
KR20100102495A (en) | 2010-09-24 |
JP5490155B2 (en) | 2014-05-14 |
US9126898B2 (en) | 2015-09-08 |
JP2012520294A (en) | 2012-09-06 |
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US20130253218A1 (en) | 2013-09-26 |
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