WO2016055819A1 - Process for the preparation of treprostinil - Google Patents
Process for the preparation of treprostinil Download PDFInfo
- Publication number
- WO2016055819A1 WO2016055819A1 PCT/HU2015/000065 HU2015000065W WO2016055819A1 WO 2016055819 A1 WO2016055819 A1 WO 2016055819A1 HU 2015000065 W HU2015000065 W HU 2015000065W WO 2016055819 A1 WO2016055819 A1 WO 2016055819A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ppm
- formula
- group
- stands
- alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 65
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 title claims abstract description 62
- 229960005032 treprostinil Drugs 0.000 title claims abstract description 56
- 230000008569 process Effects 0.000 title claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000000543 intermediate Substances 0.000 claims abstract description 7
- -1 tetrahydropyranyl- Chemical group 0.000 claims description 244
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 143
- 150000001875 compounds Chemical class 0.000 claims description 126
- 125000006239 protecting group Chemical group 0.000 claims description 80
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 61
- 239000011541 reaction mixture Substances 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 239000002585 base Substances 0.000 claims description 39
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 38
- 239000003054 catalyst Substances 0.000 claims description 36
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 239000013078 crystal Substances 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 22
- 239000012298 atmosphere Substances 0.000 claims description 22
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 22
- 125000002252 acyl group Chemical group 0.000 claims description 21
- 125000002560 nitrile group Chemical group 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 19
- 125000005104 aryl silyl group Chemical group 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 13
- MQIKJSYMMJWAMP-UHFFFAOYSA-N dicobalt octacarbonyl Chemical group [Co+2].[Co+2].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] MQIKJSYMMJWAMP-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 230000003647 oxidation Effects 0.000 claims description 12
- 238000007254 oxidation reaction Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 230000002829 reductive effect Effects 0.000 claims description 11
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 11
- 238000006647 Pauson-Khand annulation reaction Methods 0.000 claims description 10
- 229910000085 borane Inorganic materials 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 150000004682 monohydrates Chemical class 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 239000007818 Grignard reagent Substances 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- FMCGSUUBYTWNDP-MWLCHTKSSA-N (1s,2r)-2-(dimethylamino)-1-phenylpropan-1-ol Chemical compound CN(C)[C@H](C)[C@@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-MWLCHTKSSA-N 0.000 claims description 5
- JPVUWCPKMYXOKW-UHFFFAOYSA-N 4-phenylbenzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1C1=CC=CC=C1 JPVUWCPKMYXOKW-UHFFFAOYSA-N 0.000 claims description 5
- 238000007239 Wittig reaction Methods 0.000 claims description 5
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- XWCQLLDGXBLGMD-UHFFFAOYSA-M magnesium;pentane;bromide Chemical compound [Mg+2].[Br-].CCCC[CH2-] XWCQLLDGXBLGMD-UHFFFAOYSA-M 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 5
- 150000003751 zinc Chemical class 0.000 claims description 5
- XMDFGRGFVRKBKS-UHFFFAOYSA-N zinc;pentane Chemical compound [Zn+2].CCCC[CH2-].CCCC[CH2-] XMDFGRGFVRKBKS-UHFFFAOYSA-N 0.000 claims description 5
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 claims description 4
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 4
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 229940076133 sodium carbonate monohydrate Drugs 0.000 claims description 4
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 4
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 4
- ZUCSYVYDPCTIJI-BYNQJWBRSA-N (1s,2r,3s,4r)-4,7,7-trimethyl-2-morpholin-4-ylbicyclo[2.2.1]heptan-3-ol Chemical compound N1([C@H]2[C@@H](O)[C@]3(C)CC[C@H]2C3(C)C)CCOCC1 ZUCSYVYDPCTIJI-BYNQJWBRSA-N 0.000 claims description 3
- 238000006859 Swern oxidation reaction Methods 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 3
- 150000004795 grignard reagents Chemical class 0.000 claims description 3
- 238000006140 methanolysis reaction Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000005835 Pfitzner-Moffat oxidation reaction Methods 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- GFTXWCQFWLOXAT-UHFFFAOYSA-M magnesium;cyclohexane;bromide Chemical compound [Mg+2].[Br-].C1CC[CH-]CC1 GFTXWCQFWLOXAT-UHFFFAOYSA-M 0.000 claims description 2
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 112
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 99
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 90
- 239000000203 mixture Substances 0.000 description 81
- 235000019439 ethyl acetate Nutrition 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 31
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical class [Na+].C1=CC=C(OCC([O-])=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 IQKAWAUTOKVMLE-ZSESPEEFSA-M 0.000 description 29
- 101150041968 CDC13 gene Proteins 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- 235000019441 ethanol Nutrition 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 239000012043 crude product Substances 0.000 description 22
- 239000003480 eluent Substances 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 238000004587 chromatography analysis Methods 0.000 description 17
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- KXYGKDBONOVZOM-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene Chemical group C1=CC=CC2=C3CC=CC3=CC=C21 KXYGKDBONOVZOM-UHFFFAOYSA-N 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- OQOUDZFBMYRNCD-UHFFFAOYSA-N 3-methoxy-2-prop-2-enylbenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1CC=C OQOUDZFBMYRNCD-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000013019 agitation Methods 0.000 description 7
- 238000010586 diagram Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 0 *CC(C(CC1Cc2c3cccc2O*)=O)=C1[C@@]3O* Chemical compound *CC(C(CC1Cc2c3cccc2O*)=O)=C1[C@@]3O* 0.000 description 5
- 101100402341 Caenorhabditis elegans mpk-1 gene Proteins 0.000 description 5
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- NNJMFJSKMRYHSR-UHFFFAOYSA-M 4-phenylbenzoate Chemical compound C1=CC(C(=O)[O-])=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-M 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 101001059431 Mus musculus MAP/microtubule affinity-regulating kinase 3 Proteins 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VMKAFJQFKBASMU-KRWDZBQOSA-N (3as)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole Chemical compound C([C@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-KRWDZBQOSA-N 0.000 description 3
- QRIZNMGCIBXULQ-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene-1-carbonitrile Chemical compound C1=CC=CC2=C3C(C#N)C=CC3=CC=C21 QRIZNMGCIBXULQ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 3
- TZRUKFFDSQQSCK-UHFFFAOYSA-N 2-pent-4-ynoxyoxane Chemical compound C#CCCCOC1CCCCO1 TZRUKFFDSQQSCK-UHFFFAOYSA-N 0.000 description 3
- 101100495328 Mus musculus Cdk7 gene Proteins 0.000 description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- NUKZAGXMHTUAFE-UHFFFAOYSA-N methyl hexanoate Chemical compound CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000011916 stereoselective reduction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- LQZCYXCHWNQBKX-UHFFFAOYSA-N 1-dimethoxyphosphorylheptan-2-one Chemical compound CCCCCC(=O)CP(=O)(OC)OC LQZCYXCHWNQBKX-UHFFFAOYSA-N 0.000 description 2
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 2
- YEJOEVSVZNHDBJ-UHFFFAOYSA-N 2-oxoheptyl dihydrogen phosphate Chemical compound CCCCCC(=O)COP(O)(O)=O YEJOEVSVZNHDBJ-UHFFFAOYSA-N 0.000 description 2
- HWLHJDIDFDIRDN-UHFFFAOYSA-N 3-(methoxymethoxy)prop-1-yne Chemical compound COCOCC#C HWLHJDIDFDIRDN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BYKKMWRTDLCRDK-FPWWFTSNSA-N C1(=CC=CC=C1)C1=CC=C(C(=O)OC2CC3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2CCC=O)C=C1 Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)OC2CC3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2CCC=O)C=C1 BYKKMWRTDLCRDK-FPWWFTSNSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- QGIIXIVQLXMYGX-RRGSLLCRSA-N [(1R,9aS)-5-methoxy-1-[3-(oxan-2-yloxy)propyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)OC2CC3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2CCCOC2OCCCC2)C=C1 QGIIXIVQLXMYGX-RRGSLLCRSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000005905 alkynylation reaction Methods 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 229940001593 sodium carbonate Drugs 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- DOKGVQFKRMEKJX-NWSYQISNSA-N (1R,3aS,9aS)-1-(3-hydroxyoctyl)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol Chemical compound OC(CC[C@H]1C(C[C@H]2[C@@H]1CC1=CC=CC(=C1C2)OC)O)CCCCC DOKGVQFKRMEKJX-NWSYQISNSA-N 0.000 description 1
- AKFOTXBERWQGBT-HMHUYEIWSA-N (1R,3aS,9aS)-1-[(E)-3-hydroxyoct-1-enyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol Chemical compound OC(/C=C/[C@H]1C(C[C@H]2[C@@H]1CC1=CC=CC(=C1C2)OC)O)CCCCC AKFOTXBERWQGBT-HMHUYEIWSA-N 0.000 description 1
- UMWSHCQKRDXYNE-CCQOOCRRSA-N (1S,2R,9aS)-5-methoxy-1-(methoxymethoxymethyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol Chemical compound COC1=C2CC3[C@H](CC2=CC=C1)[C@H]([C@@H](C3)O)COCOC UMWSHCQKRDXYNE-CCQOOCRRSA-N 0.000 description 1
- UTGPMEMKMRVGNE-HUTLKBDOSA-N (1r,2r,3as,9as)-1-[(3s)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalene-2,5-diol Chemical compound C1=CC=C2C[C@@H]3[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]3CC2=C1O UTGPMEMKMRVGNE-HUTLKBDOSA-N 0.000 description 1
- YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 description 1
- PPNCOQHHSGMKGI-UHFFFAOYSA-N 1-cyclononyldiazonane Chemical compound C1CCCCCCCC1N1NCCCCCCC1 PPNCOQHHSGMKGI-UHFFFAOYSA-N 0.000 description 1
- BLXSFCHWMBESKV-UHFFFAOYSA-N 1-iodopentane Chemical compound CCCCCI BLXSFCHWMBESKV-UHFFFAOYSA-N 0.000 description 1
- RHWRWEUCEXUUAV-ZSESPEEFSA-N 2-[[(1r,2r,3as,9as)-2-hydroxy-1-[(3s)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetic acid;2-(2-hydroxyethylamino)ethanol Chemical class OCCNCCO.C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 RHWRWEUCEXUUAV-ZSESPEEFSA-N 0.000 description 1
- ACMQFLCUSWMWKH-UHFFFAOYSA-N 2-oxoheptylphosphonic acid Chemical compound CCCCCC(=O)CP(O)(O)=O ACMQFLCUSWMWKH-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- LSGDKPNKOYLZAO-GATTVKALSA-N CCCCC[C@@H](/C=C/C(C)(CC1)[C@@H](C2)[C@H]1Cc1c2cccc1OC)O Chemical compound CCCCC[C@@H](/C=C/C(C)(CC1)[C@@H](C2)[C@H]1Cc1c2cccc1OC)O LSGDKPNKOYLZAO-GATTVKALSA-N 0.000 description 1
- PAJMKGZZBBTTOY-GAQDBVNISA-N CCCCC[C@@H](CCC([C@@H](C1)O)[C@@H](Cc2ccc3)C1Cc2c3OCC(O)=O)O Chemical compound CCCCC[C@@H](CCC([C@@H](C1)O)[C@@H](Cc2ccc3)C1Cc2c3OCC(O)=O)O PAJMKGZZBBTTOY-GAQDBVNISA-N 0.000 description 1
- CAZRMTNYOYIFKX-RSPOEFSDSA-N CCCCC[C@@H](CC[C@@H](CC1)[C@@H](C2)[C@H]1Cc1c2cccc1OC)O Chemical compound CCCCC[C@@H](CC[C@@H](CC1)[C@@H](C2)[C@H]1Cc1c2cccc1OC)O CAZRMTNYOYIFKX-RSPOEFSDSA-N 0.000 description 1
- CECXXUOYPXRZGL-UHFFFAOYSA-N COc1c(CC=C)c(C(C#CCCCOC2OCCCC2)O)ccc1 Chemical compound COc1c(CC=C)c(C(C#CCCCOC2OCCCC2)O)ccc1 CECXXUOYPXRZGL-UHFFFAOYSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910000881 Cu alloy Inorganic materials 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- BUIQRTDBPCHRIR-UHFFFAOYSA-L O[Cr](Cl)(=O)=O Chemical compound O[Cr](Cl)(=O)=O BUIQRTDBPCHRIR-UHFFFAOYSA-L 0.000 description 1
- 208000020193 Pulmonary artery hypoplasia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- YPJPBEBYJFFXIV-JYAGOLQOSA-N [(1R,2R,3aS,9aS)-1-[(E,3S)-3-hydroxyoct-1-enyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)O[C@@H]2C[C@H]3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2\C=C\[C@H](CCCCC)O)C=C1 YPJPBEBYJFFXIV-JYAGOLQOSA-N 0.000 description 1
- MGHQBQYRVDMFNH-NWGOQBBVSA-N [(1R,2R,3aS,9aS)-5-methoxy-1-[(E)-3-oxooct-1-enyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)O[C@@H]2C[C@H]3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2\C=C\C(CCCCC)=O)C=C1 MGHQBQYRVDMFNH-NWGOQBBVSA-N 0.000 description 1
- JJAMRZCKWFTTOP-NNTYPUFZSA-N [(1S,2R,9aS)-1-(hydroxymethyl)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)O[C@@H]2CC3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2CO)C=C1 JJAMRZCKWFTTOP-NNTYPUFZSA-N 0.000 description 1
- NZWHMJXLGDCEGV-FFURYCECSA-N [(1S,2R,9aS)-5-methoxy-1-(methoxymethoxymethyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate Chemical compound C1(=CC=CC=C1)C1=CC=C(C(=O)O[C@@H]2CC3[C@H](CC4=CC=CC(=C4C3)OC)[C@H]2COCOC)C=C1 NZWHMJXLGDCEGV-FFURYCECSA-N 0.000 description 1
- RPODCFZVMYBRFX-YUCZZJJKSA-N [Si](C)(C)(C(C)(C)C)O[C@H]1C=2C(CC3=C(C=CC=C13)OC)CC(C=2CCCOC1OCCCC1)=O Chemical compound [Si](C)(C)(C(C)(C)C)O[C@H]1C=2C(CC3=C(C=CC=C13)OC)CC(C=2CCCOC1OCCCC1)=O RPODCFZVMYBRFX-YUCZZJJKSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000006241 alcohol protecting group Chemical group 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000010405 anode material Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 229950011260 betanaphthol Drugs 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical compound [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- PBMHCIQUGUOGFB-KHYDEXNFSA-N ethyl 2-[[(1r,2r,3as,9as)-2-hydroxy-1-[(3s)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetate Chemical compound C1=CC=C(OCC(=O)OCC)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PBMHCIQUGUOGFB-KHYDEXNFSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical group CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- BRHPHJOLNONZCH-UHFFFAOYSA-N heptylphosphonic acid methyl hexanoate Chemical compound CCCCCC(=O)OC.CCCCCCCP(O)(O)=O BRHPHJOLNONZCH-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960001726 treprostinil sodium Drugs 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/243—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/54—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings
- C07C13/547—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings at least one ring not being six-membered, the other rings being at the most six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/37—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with a hydroxy group on a condensed system having three rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/05—Preparation of ethers by addition of compounds to unsaturated compounds
- C07C41/06—Preparation of ethers by addition of compounds to unsaturated compounds by addition of organic compounds only
- C07C41/08—Preparation of ethers by addition of compounds to unsaturated compounds by addition of organic compounds only to carbon-to-carbon triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/48—Preparation of compounds having groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/30—Compounds having groups
- C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
- C07C45/305—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation with halogenochromate reagents, e.g. pyridinium chlorochromate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/50—Use of additives, e.g. for stabilisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
-
- 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 invention relates to the preparation of treprostinil of formula I and its amorph, anhydrate, monohydrate and polyhydrate salts given with bases, to treprostinil intermediates of general formulae III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV and XV and to their preparation.
- Treprostinil is a synthetic prostacyclin derivative with thrombocyte aggregation inhibitory and vasodilatory activity, it can be administered in subcutaneous, intravenous, inhalatory or oral forms.
- FIG. 1 is shown at the end of the description part, prior to the Examples.
- the ring closure is performed by Pauson-Khand cyclisation.
- the chain with the triple bond consists of at least seven carbon atoms.
- the molecule resulting from the Pauson- Khand cyclisation already contains the treprostinil side-chain ( Figure 3).
- Z ( 1>3 , 4 )' and Y(i, 2)3 )' stand for hydrogen or deuterium
- Rl ' is pentyl group optionally containing one or more deuterium.
- the coupling of the side chain containing the triple bond to the aldehyde is carried out in the presence of chiral catalyst ((+)-N-methylephedrine), in that way the chiral alcohol is obtained in one step, without the formation of the racemic alcohol. In this way, one oxidation step and the stereoselective reduction are eliminated.
- chiral catalyst ((+)-N-methylephedrine)
- the side chain with the triple bond contains, in that case too, at least seven carbon atoms.
- the molecule resulting from the Pauson-Khand cyclisation will already contain the treprostinil side-chain.
- the high purity treprostinil can be transformed with various bases into the desired high purity salts.
- the benzindene derivative is alkylated with bromoacetic acid methyl ester and the resulting treprostinil methyl ester is hydrolyzed without purification into treprostinil by use of potassium hydroxide in methanol-water solvent mixture.
- the subject of the invention is a method for the preparation of treprostinil of formula I and its amorph, anhydrate salts given with bases, as well as the monohydrates and polyhydrates thereof
- R 1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- group- ,
- R 2 represents -(CH 2 ) n Y, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR 5 or -COOR 5 group, wherein R 5 means C alkyl-, tetrahydropyranyl-, tri(Ci. 4 )alkylsilyl- or (C 1-4 )alkyl-di(C 6- io)arylsilyl- group and n stands for 1,2,3,4 -, al .) is reacted in the presence of Grignard reagent, and the resulting compound of the general formula XV
- R 4 represents a protective group containing silicium atom, trityl-, methoxytntyl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or Ci -13 acyl- group, with the proviso that the R 4 protective group must be selectively removable from R 2 , and R 1 must be selectively removable from R 4 , f.) from the resulting com ound of the general formula VIII
- R 6 stands for C 1-4 alkyl- or phenyl- group -
- R 1 protective group preferably methoxymethyl-, methoxyethoxymethyl-, or
- R protective group methyl group a protective group containing silicium atom, preferably tert-butyldimethylsilyl group, as R 4 protective group p-phenylbenzoyl group may be applied.
- the invention furthermore relates to the preparation of the optically active compounds of the general formula II
- R represents -(CH 2 ) n Y, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR 5 or -COOR 5 group, wherein R 5 means C 1-4 alkyl-, tetrahydropyranyl-, th(C ⁇ ⁇ )alkylsilyl- or (C 1 - 4)alkyl-di(C6-i 0 )arylsilyl- group and n stands for 1,2,3,4.
- the compounds of the general formula II. can be prepared so that a compound of the general formula III
- R 4 represents a protective group containing silicium atom, trityl-, methoxytntyl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or Cj -13 acyl- group, with the proviso that the R 4 protective group must be selectively removable from R - is removed.
- Hydrogenation of the compound of the general formula III is carried out in the presence of catalyst.
- Pd/C catalyst preferably Pd/C catalyst may be applied.
- R 2 represents -(CH 2 ) n Y, where
- Y stands for hydrogen atom, halogen atom, phenyl-, -OR 5 or -COOR 5 group, wherein
- R 5 means C 1-4 alkyl-, tetrahydropyranyl-, tri(C M )alkylsilyl- or (Ci -4 )alkyl-di(C 6-1 o)arylsilyl- group and n stands for 1,2,3,4 -, with the proviso that R 5 in -COOR 5 cannot stay for C alkyl.
- the compounds of the general formula III can be prepared so that the R 4 protective group of the compounds of the general formula IVa.
- R has the meaning as defined above and
- R 4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C 1-13 acyl- group, with the proviso that the R 4 protective group must be selectively removable from R 2 - R 4 is removed.
- the R protective group containing the silicium atom is preferably phenyldimethylsilyl-, triethylsilyl-, triisopropylsilyl-, tert-butyldimethylsilyl- or tert-butyldiphenylsilyl- group.
- R represents -(CH 2 ) n Y, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR 5 or -COOR 5 group, wherein R 5 means C alkyl-, tetrahydropyranyl-, tri(C 1-4 )alkyIsilyl- or (Ci-4)alkyl-di(C -1 o)arylsilyl- group,
- n 1,2,3,4,
- R 4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C 1-13 acyl- group, with the proviso that the R 4 protective group must be selectively removable from R , and
- novel compounds are novel compounds.
- the novel compounds of the general formula IVa are novel compounds.
- R represents -(CH 2 ) n Y, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR 5 or -COOR 5 group, wherein R 5 means C alkyl-, tetrahydropyranyl-, tri(Cj-4)alkylsilyl- or (CM)alkyl-di(C6-io)arylsilyl- group, n stands for 1,2,3,4, and
- R 4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C 1-13 acyl- group, with the proviso that the R 4 protective group must be selectively removable from R ,
- Reduction of the compound of formula V is performed with borane compound, in the presence of oxazaborolidine catalyst.
- borane compound catecholborane borane-diethylaniline complex, borane-dimethyl sulfide complex, preferably borane-dimethyl sulfide complex is applied.
- novel compounds of the general formula V can be prepared so that a compound of the general formula Via.
- R 2 represents -(CH 2 ) n Y, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR 5 or -COOR 5 group, wherein R 5 means Cu alkyl-, tetrahydropyranyl-, tri(C 1- 4)alkylsilyl- or (C 1-4 )alkyl-di(C 6- io)arylsilyl- group,
- n 1,2,3,4,
- R 4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C 1-13 acyl- group, with the proviso that the R 4 protective group must be selectively removable from R 2 ,
- R 2 and R 4 have the meanings as defined above -, is reacted with an organic metal reagent, in the presence of chiral catalyst.
- R 2 represents -(CH 2 ) n Y, where
- Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR 5 or -COOR 5 group, wherein R 5 means C alkyl-, tetrahydropyranyl-, tri(C 1-4 )alkylsilyl- or
- n 1,2,3,4,
- R 4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C 1-13 acyl- group, with the proviso that the R 4 protective group must be selectively removable from R 2 ,
- x, R 2 and R 4 have the meanings as defined above-, is oxidized.
- Oxidation of the compound of formula VII is carried out with PCC (pyridinium chlorochromate) or under Swern conditions (oxalyl chloride/DMSO/organic base) or with TEMPO (2,2,6,6- tetramethyl-l-piperidinyloxy free radical), or under Pfitzner-Moffat conditions (DCC).
- PCC pyridinium chlorochromate
- Swern conditions oxalyl chloride/DMSO/organic base
- TEMPO 2,2,6,6- tetramethyl-l-piperidinyloxy free radical
- novel compounds of the general formula VII can be prepared so that the R 1 protective group of a compound of the general formula VIII
- R 1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl,- ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- group, with the proviso that the R 1 protective group must be selectively removable from R 2 and
- the protective group R 1 which contains silicium atom is preferably phenyldimethylsilyl-, triethylsilyl-, triisopropylsilyl-, tert-butyldimethylsilyl- or tert-butyldiphenylsilyl- group.
- novel compounds of the general formula VIII can be prepared so that a compound of the general formula EX.
- R 1 and R 2 have the meanings as defined above-, is reacted with a compound suitable for the introduction of a group R 4 .
- novel compounds of the general formula IX can be prepared so that a compound of the general formula X
- Reduction of the compound of the general formula X can be carried out with diisobutylaluminum hydride, lithium aluminum hydride, aluminum isopropylate, or sodium borohydride, preferably sodium borohydride.
- novel compounds of the general formula X can be prepared so that a compound of the general formula XI
- R 3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl,- ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or Ci -13 acyl- group - is catalytically hydrogenated, and
- Pd/C catalyst for the hydrogenation of the compound of formula XI as catalyst Pd/C catalyst or platinum oxide, preferably Pd/C catalyst may be used.
- novel compounds of the general formula XI can be prepared so that a compound of the general formula XII
- R 1 , R 2 and R 3 have the meanings as defined above - is subjected to intramolecular cyclisation.
- the Pauson-Khand cyclisation method is applied.
- the Pauson- Khand cyclisation is performed using dicobalt octacarbonyl.
- Dicobalt octacarbonyl may be applied in equimolar, or less than equimolar or more than equimolar ratios.
- the reaction is preferably performed in carbon monoxide atmosphere using ethyl acetate as solvent.
- novel compounds of the general formula XII can be prepared so that a compound of the general formula XIII
- R 1 and R 2 have the meanings as defined above - is reacted with a compound suitable for the introduction of group R .
- novel compounds of the general formula XIII can be prepared so that a.) a compound of the general formula XIV
- R has the meaning as defined above -, is reacted with a compound of the general formula XVII
- R 1 and x have the meanings as defined above - in the presence of a chiral base and zinc salt.
- Reduction of the compound of the general formula XIV is carried out with borane compound, in the presence of chiral oxazaborolidine catalyst.
- borane compound borane-dimethyl sulfide complex, catecholborane or borane-diethylaniline complex, preferably borane-dimethyl sulfide complex, as chiral base, chiral aminoalcohols or diamines, preferably (+)-N-methylephedrine may be applied.
- zinc salt preferably zinc triflate may be applied.
- novel compounds of the general formula XIV can be prepared so that a compound of the general formula XV
- x, R and R have the meanings as defined above -, is oxidized.
- Oxidation of the compound of formula XV is carried out with PCC (pyridinium chlorochromate) or under Swern reaction conditions (oxalyl chloride/DMSO/organic base).
- novel compounds of the general formula XV can be prepared so that a compound of the general formula XVI
- R has the meaning as defined above -, is reacted with a compound of the general formula XVII
- Grignard reagent methyl-, ethyl-, propyl-, butyl-, cyclohexyl- magnesium bromide, preferably methylmagnesium bromide may be applied.
- a further subject of our invention is novel method for the preparation of the amorph, anhydrate, monohydrate and polyhydrate salts of treprostinil of formula I given with bases
- Treprostinil salts among them treprostinil sodium salt, in general form are described in
- WO 2012/088607 (Alphora) describes a new process for the preparation of treprostinil sodium salt in that treprostinil is dissolved in a water-miscible organic solvent to form treprostinil solution, than the solution is reacted with an aqueous solution containing an alkali metal cation to form a reaction mixture containing the treprostinil salt, the salt is allowed to crystallization and the salt formed is collected.
- the amorph, anhydrate, monohydrate and polyhydrate salts of treprostinil of formula I given with bases are prepared in a way that treprostinil is dissolved in polar solvent, the solid base is added to the solution, the reaction mixture is agitated and when salt formation is completed the solution is filtered, concentrated, the solvent of the concentrate is exchanged for the organic solvent of the crystallisation and the treprostinil salt is crystallized.
- a solvent-free organic or inorganic base which contains the cation of the desired salt for example an organic or inorganic base containing alkali metal cation or alkali earth-metal cation, e.g. sodium carbonate monohydrate, sodium hydrogen carbonate or sodium methylate, preferably a hydrate of sodium carbonate may be applied.
- alkali metal cation or alkali earth-metal cation e.g. sodium carbonate monohydrate, sodium hydrogen carbonate or sodium methylate, preferably a hydrate of sodium carbonate
- reaction mixture is agitated in an inert atmosphere until salt formation is completed.
- aqueous ether-, ester- or ketone-type solvent i.e. as ether-type solvent an open-chain or branched simple or mixed ether, preferably tert-butyl methyl ether may be applied.
- Crystallisation is preferably carried out at a temperature between 50°C - (- 40°C).
- the organic solvent of crystallisation is a water-free ether-, ester- or ketone-type solvent
- the amorphous treprostinil sodium salt is obtained which is a new compound.
- treprostinil sodium salt anhydrate (Form B) can be prepared by carrying out the above process till the crystallisation step and performing the crystallisation at 60- 100°C or in vacuum.
- Another possible method is that the sodium salt monohydrate is taken up and stirred at 60-90°C for 1-6 hours in a solvent which does not, or only sparingly dissolves the salt.
- solvent preferably hexane, heptane, toluene, ethyl acetate may be applied.
- the propargyl alcohol is protected with methoxymethyl group.
- the protected propargyl alcohol (XVII) is reacted with 2-allyl-3-methoxybenzaldehyde (XVI) in the presence of methylmagnesium bromide Grignard reagent.
- the thus obtained racemic alcohol (XV) is oxidized.
- the oxidation is carried out e.g. by the Swern oxidation method or by oxidation with chromium(VI).
- the stereoselective reduction may be carried out e.g. with borane-dimethyl sulfide complex in the presence of Corey catalyst.
- the chiral alcohol XIII may directly be prepared by reacting the protected propargyl alcohol (XVII) with 2-allyl-3-methoxybenzaldehyde (XVI) in the presence of chiral base, e.g. (+)-N- methylephedrine and zinc triflate.
- chiral base e.g. (+)-N- methylephedrine and zinc triflate.
- the silyl ether (XII) is cyclized in Pauson-Khand reaction in the presence of dicobalt octacarbonyl.
- the tricycle (XI) is formed by incorporation of a CO molecule.
- the cyclisation can be carried out using equimolar amount of dicobalt octacarbonyl, or more preferably with catalytic amount of dicobalt octacarbonyl under carbon monoxide atmosphere.
- the silyloxy group is removed by catalytic hydrogenation and the double bond of the five- membered ring is saturated.
- the stereostructure of the tricyclic ketone (X) is formed by isomerisation with base (diazabicyclononane/ethanol).
- the methoxymethyl protecting group is cleaved by treatment with acid (VII).
- the primary hydroxyl group is oxidized (VI).
- enone V is reduced by a selective reduction method, e.g. with borane-dimethyl sulfide complex, in the presence of Corey catalyst.
- the p-phenylbenzoyl protecting group of the resulting compound of formula IV is removed by methanolysis, in the presence of base. Saturation of the double bond of the enol of formula III by catalytic hydrogenation results the benzindene derivative of formula II.
- 2-pent-4-ynoxytetrahydropyran is used as starting material, instead of the protected propargyl alcohol.
- the side-chain is built out stereoselectively in the presence of chiral catalyst, by reaction with dipentylzinc or
- the benzindene of formula II is the key-intermediate to treprostinil, it is transformed to treprostinil by known chemical steps.
- the first chemical step is the cleavage of the methyl ether. Removal of the methyl group is carried out with a mercaptan, in the presence of aluminum halide.
- the next step is the alkylation of the aromatic hydroxyl group with a haloacetic acid ester, bromo- or chloroacetic acid ethyl- or methyl ester.
- a haloacetic acid ester bromo- or chloroacetic acid ethyl- or methyl ester.
- the trihydroxy derivative alkylated with bromoacetic acid ethyl ester.
- hydrolysis is carried out with aqueous sodium hydroxide solution, in tetrahydrofuran.
- treprostinil is dissolved in ethanol and solid sodium carbonate
- the solution is filtered through microfilter, the ethanol is exchanged for tert-butyl methyl ether which has been saturated with water and the treprostinil sodium salt is crystallized at room temperature.
- the construction of the side-chain is realized by well-scalable and robust chemical steps (Wittig- or modified Wittig reaction) which are used in the prostaglandin chemistry, or carried out stereoselectively by use of organic metal compound, in the presence of chiral catalyst.
- the enone obtained in the Wittig reaction can be transformed into the desired enantiomer in stereoselective reaction, in a good yield.
- the applied p-phenylbenzoyl group (PPB-group) is well detectable in UV.
- the PPB-group enhances the crystallisation ability of the intermediates and thus helps their purification.
- TBDMS tertiary-butyldimethylsilyl
- PCC pyridinium chlorochromate Corey catalyst:
- Pi and P 2 alcohol-protecting groups
- R (CH 2 )mC0 2 Ri
- the mixture is stirred at room temperature.
- the mixture is cooled to 0°C and NaHS0 4 (sodium hydrogen sulfate) solution is added to it.
- NaHS0 4 sodium hydrogen sulfate
- the phases are separated, the aqueous layer is extracted with ethyl acetate.
- the united organic phase is washed with NaHC0 3 (sodium hydrogen carbonate) solution and dried over sodium sulfate.
- the drying material is filtered off, the filtrate solution is evaporated in vacuum.
- the crude product is taken into the next step, without purification.
- TREP-1 is added at -75 ⁇ 85 °C. After 1 hour of stirring the reaction mixture is quenched with 621 ml of triethylamine and NaHS0 4 solution. The organic phase is extracted with dichloromethane, the united organic phase is washed with 1M NaHC0 3 solution. The crude product is purified by chromatography on silica gel.
- the reaction vessel is charged with 216 mg (0.59 mmol) of zinc triflate and 82 mg (0.45 mmol) of (+)-N-methylephedrine, flushed with nitrogen gas for 10 minutes, then 1 ml of dist. toluene and 63 microl (0.45 mmol) of triethylamine are added.
- the reaction mixture is stirred at room temperature for 1 hour, then 250 microl (0.45 mmol) of TREPO-1 solution and after 15 minutes of stirring 24 microl of VPK-5 (2-allyl-3-methoxybenzaldehyde) (0.14 mmol) are added. Following 24 hours of stirring at room temperature, the reaction mixture is quenched with 1 ml of saturated NH4CI solution.
- the aqueous phase is extracted with toluene, the united organic phase is washed consecutively with NaHC0 3 solution and saturated NaCl solution, then evaporated.
- TREP-4 93 g (0.24 mol) of TREP-4 is dissolved under nitrogen atmosphere in 930 ml of ethyl acetate and to the solution 85.5 g (0.25 mol) of dicobalt octacarbonyl is added.
- the reaction mixture is stirred at room temperature for 2.5 hours and then warmed to 60-70°C.
- the evolving carbon monoxide gas is lead away in closed system.
- the mixture is cooled to room temperature and air is bubbled through for 12 hours.
- the reaction mixture is filtered, the precipitate is washed with ethyl acetate.
- the united filtrate solution is evaporated in vacuum.
- the crude product is chromatographed on silica gel using hexane: ethyl acetate eluent.
- TREP-5 63 g (0.15 mol) of TREP-5 is dissolved in 630 ml of ethyl acetate and 19 ml of pyridine is added to the solution.
- the reaction mixture is hydrogenated over 25 g of 10% palladium on charcoal catalyst under 6 bar pressure.
- the catalyst is filtered off and washed with ethyl acetate.
- the filtrate is evaporated in vacuum.
- the crude product is chromatographed on silica gel using hexane: ethyl acetate mixture as eluent. The evaporated main fraction is crystallized at 0°C from hexane-ethyl acetate mixture and collected by filtration.
- the evaporated mother liquor is, in order of isomerisation, dissolved in the mixture 100 ml of toluene and 60 ml of ethanol. 12 ml of DBN reagent (2,3,4,6,7,8-hexahydropyrrolo[l,2-a]pyrimidine) is added to it at 0°C and the mixture is agitated for 15 minutes. The reaction mixture is then quenched with NaHS0 4 solution, extracted with tert-butyl methyl ether and evaporated. The residue is chromatographed on silica gel using hexane:ethyl acetate mixture as eluent. The evaporated main fraction is crystallized at 0°C from hexane-ethyl acetate mixture. The crystals are collected by filtration and united with earlier gained crystals.
- Method lil 140 ml of 5 M hydrochloric acid is added to the mixture and stirred at 45-50°C.
- Method li2. 14 g of p-toluene sulfonic acid monohydrate is added to the mixture and stirred at 45-50°C.
- the mixture is neutralized with NaHC0 3 solution, the organic solvents are distilled off.
- the residue is extracted with ethyl acetate, the united organic phase is washed with water, dried over sodium sulfate.
- the crude product is chromatographed on silica gel, using hexane: ethyl acetate mixture as eluent.
- TREP-9 20 g (46.7 mmol) of TREP-9 is dissolved in an inert atmosphere in 200 ml water-free toluene.
- 30 g of dicyclohexylcarbodiimide (DCC) and 10 ml of dimethyl sulfoxide in phosphoric acid are added.
- the reaction mixture is heated to 50°C and in portions, a further 5 ml of dimethyl sulfoxide in phosphoric acid are added.
- the reaction mixture is cooled to -10°C and at that temperature 4 g (71 mmol) of potassium hydroxide and then 10.9 g (49 mmol) of 2-oxo-heptylphosphoric acid dimethyl ester in toluene solution are added.
- the mixture is poured onto acid solution.
- the precipitated crystals are filtered off and washed.
- the phases of the filtrate are separated, the organic phase is washed with 1M sodium hydrogen carbonate solution and then with diluted hydrochloric acid solution.
- the organic phase is evaporated and purified by chromatography on silica gel column using toluene: hexane eluent.
- the organic phase is evaporated and purified by chromatography on silica gel column using toluene :hexane eluent.
- LDA diisopropylamide
- the aqueous phase is extracted with toluene, the organic phase is dried over Na 2 S0 4 , the drying material is filtered off, the filtrate is evaporated and purified by chromatography on silica gel column (using hexane: tert-butyl methyl ether mixture eluent). The main fraction is crystallized from the mixture of hexane and tert-butyl methyl ether. The precipitated crystals are filtered off, washed and dried.
- Treprostinil sodium salt monohydrate is agitated in suspension at 60-90 °C for 1-6 hours in a solvent which does not or only sparingly dissolves it.
- the solvent may be e.g. hexane, heptane, toluene or ethyl acetate.
- Treprostinil sodium salt monohydrate (formcutA") is kept in manipulator under an atmosphere of 60% moisture content for 48 hours, or treprostinil sodium salt monohydrate is kept under air for 5-8 days.
- Treprostinil sodium salt anhydrate (form aromatic) is kept in manipulator under an atmosphere of 60% moisture content for 48 hours, or is kept under air for 5-8 days.
- TGA Termogravimetric analysis
- the mixture is quenched with 1M NaHSC ⁇ 4 solution, the aqueous phase is extracted with ethyl acetate, the united organic phase is washed with 0.5M NaHC0 3 solution and 15% NaCl solution, dried and concentrated to 2.4 kg. The concentrated crude product is taken into the next step without purification.
- the crude product is purified by chromatography on silica gel column using hexane: ethyl acetate mixtures as eluent.
- the evaporated main fraction is crystallized in diisopropyl ether: hexane mixture.
Abstract
The invention provides a new process for the preparation of treprostinil of formula (I) and its salts using several new intermediates during the building of the ringsystem.
Description
PROCESS FOR THE PREPARATION OF TREPROSTINIL
The invention relates to the preparation of treprostinil of formula I and its amorph, anhydrate, monohydrate and polyhydrate salts given with bases, to treprostinil intermediates of general formulae III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV and XV and to their preparation.
Treprostinil is a synthetic prostacyclin derivative with thrombocyte aggregation inhibitory and vasodilatory activity, it can be administered in subcutaneous, intravenous, inhalatory or oral forms.
Its therapeutic field is the treatment of pulmonary arterial hypertension (Pulmonary Arterial Hypertension, PAH). (Drugs, 2012, 72 (18) 2351-2363).
For the construction of the benzindene structural part of treprostinil several methods are known. A summary of the hitherto described synthetic routes has been published in Drugs of the Future, 2001, 26 (4) 364-374.
Comparing the synthetic routes, the Pauson-Khand cyclisation - described in patent specification WO99/21830 Al - seems to be the most effective method for the construction of the ring system.
According to the example disclosed in patent specification WO 99/21830 Al (US 6441245 Bl), the benzindene key intermediate is synthesized by the reaction route outlined in Figure 1.
Figure 1 is shown at the end of the description part, prior to the Examples.
The key intermediate is then transformed into treprostinil by known chemical reactions as demonstrated in Figure 2, shown at the end of the description part, prior to the Examples.
In patent specification WO 2009/158010 Al the preparation of deuterated treprostinil derivatives is disclosed.
The ring closure is performed by Pauson-Khand cyclisation. In that case, too, the chain with the triple bond consists of at least seven carbon atoms. The molecule resulting from the Pauson- Khand cyclisation already contains the treprostinil side-chain (Figure 3).
Figure 3
where Z (1>3,4)' and Y(i,2)3)' stand for hydrogen or deuterium
where Rl ' is pentyl group optionally containing one or more deuterium.
The differences between the methods described in patent specifications WO 2011/153363 Al and WO 99/21830 Al are as follows:
The coupling of the side chain containing the triple bond to the aldehyde is carried out in the presence of chiral catalyst ((+)-N-methylephedrine), in that way the chiral alcohol is obtained in one step, without the formation of the racemic alcohol. In this way, one oxidation step and the stereoselective reduction are eliminated.
The amount of the dicobalt octacarbonyl has been decreased (instead of equimolar ratio only 2-15 mol% are used) and the ring closure is carried out under carbon monoxide pressure. The full synthesis scheme is presented in Figure 4, at the end of the description part, prior to the Examples.
The synthesis described in patent specification WO 2012/009816 Al also utilises the Pauson- Khand cyclisation for the formation of the benzindene ring. Novelty in the synthesis is that the phenolic hydroxyl group is protected with p-methoxybenzyl (PMB) protective group.
The side chain with the triple bond contains, in that case too, at least seven carbon atoms.
The molecule resulting from the Pauson-Khand cyclisation will already contain the treprostinil side-chain.
The full synthesis scheme is presented in Figure 5, at the end of the description part, before the Examples.
Synthesis of a treprostinil salt is given in detail in patent specification WO 2009/078965 (PCT/US2008/013686) (United Therapeutics). It describes the preparation of the crystalline diethanolamine salt.
According to the method the benzindenenitrile is obtained via alkylation of the aromatic hydroxyl group of the benzindene structure. (Figure 6)
Figure 6
The benzindenenitrile is hydrolyzed to treprostinil and transformed, without isolation, into the crystalline diethanolamine salt. (Figure 7)
Fi ure 7
1. Diethanolamine
EtOH, EtOAc
2. Heptane
Fi ure 8
After separation of the phases the ethyl acetate phase is evaporated, the residue is crystallized with aqueous ethanol, collected by filtration and dried.
Purification through the diethanolamine salt is so effective that purification of the
benzindenenitrile derivative by chromatography is not needed.
The high purity treprostinil can be transformed with various bases into the desired high purity salts.
Detailed description of the sodium salt formation is described in patent specification WO
2012/088607.
According to the description the benzindene derivative is alkylated with bromoacetic acid methyl ester and the resulting treprostinil methyl ester is hydrolyzed without purification into treprostinil by use of potassium hydroxide in methanol-water solvent mixture.
The reaction mixture is then acidified with hydrochloric acid, the precipitated white solid is filtered off, washed with methanol-water mixture, dried in vacuum and transformed into the sodium salt. (Figure 9)
Figure 9
We aimed to elaborate a method where the chiral center in the lower chain is built out only at the end of the synthesis and the method is robust and well scalable.
The subject of the invention is a method for the preparation of treprostinil of formula I and its amorph, anhydrate salts given with bases, as well as the monohydrates and polyhydrates thereof
a.) a compound of the general formula XVII
XVII
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- group- ,
with the proviso that the R1 protective group must be selectively removable from R2 and R4, and x represents 0 or 2 -, and a compound of the general formula XVI
- where in the formula
R2 represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(Ci.4 )alkylsilyl- or (C1-4 )alkyl-di(C6-io)arylsilyl- group and n stands for 1,2,3,4 -, al .) is reacted in the presence of Grignard reagent, and the resulting compound of the general formula XV
- where in the formula the meanings of x, R1 and R2 are as defined above - is oxidized, and the resulting compound of the general formula XIV
- where in the formula the meanings of x, R1 and R2 are as defined above - is selectively reduced, or
a2.) are reacted in the presence of chiral base and zinc salt, and the compound of the general formula XIII obtained in step al .)
- where in the formula the meanings of x, R and R are as defined above - is reacted with a compound suitable for the introduction of group R 3 - where R 3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group-, b.) the resulting compound of the general formula XII
- where in the formula the meanings of x, R1, R2 and R3 are as defined above - is subjected to intramolecular cyclisation, c.) the resulting compound of the general formula XI
- where in the formula the meanings of x, R1, R2 and R3 are as defined above - is catalytically hydrogenated, and in the case where
x=0 isomerized, d.) the resulting compound of the eneral formula X
-where in the formula the meanings of x, R1, R2 are as defined above -, is reduced, e.) the resulting compound of the general formula IX
- where in the formula the meanings of x, R1 and R2 are as defined above - is reacted with a compound suitable for the introduction of group R4 - where R4 represents a protective group containing silicium atom, trityl-, methoxytntyl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-
or Ci-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R2, and R1 must be selectively removable from R4 , f.) from the resulting com ound of the general formula VIII
- where in the formula the meanings ofx, R', R2 and R4 are as defined above - the R
protective group is cleaved in acidic medium, g) the resulting compound of the general formula VII
- where in the formula the meanings ofx, R2 and R4 are as defined above - is oxidized, h.) the resulting compound of the general formula VI
VI
- where in the formula the meanings ofx, R2 and R4 are as defined above - hi.) in the case where x means 0, is reacted in Wittig reaction with the compound of general formula
CH3-(CH2)4-CO-CH2-PO(OR6)2
- where in the formula R6 stands for C1-4 alkyl- or phenyl- group -, and
the resulting compound of the general formula V
- where in the formula the meanings ofR2 and R4 are as defined above - is selectively reduced, the protective group of the resulting compound of the general formula IVa.
- where in the formula the meaning of R is as defined above - is hydrogenated, or h2.) in the case where x means 2, is reacted with organic metal reagent in the presence of chiral catalyst, and
the protective group R4 of the resulting compound of the general formula IVb.
IVb.
- where in the formula the meanings of R2 and R4 are as defined above - then R4 is removed, i) the compound of the general formula II. obtained in steps hi .) or h2.)
- where in the formula the meaning of R is as defined above - is transformed by known method into treprostinil of formula I, and if desired, into its amorph, anhydrate, monohydrate and polyhydrate salts given with bases.
As R1 protective group preferably methoxymethyl-, methoxyethoxymethyl-, or
tetrahydropyranyl-group, as R protective group methyl group, as R protective group a protective group containing silicium atom, preferably tert-butyldimethylsilyl group, as R4 protective group p-phenylbenzoyl group may be applied.
The invention furthermore relates to the preparation of the optically active compounds of the general formula II
-where in the formula
R represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, th(C\^ )alkylsilyl- or (C1 -4)alkyl-di(C6-i0)arylsilyl- group and n stands for 1,2,3,4.
According to the invention the compounds of the general formula II. can be prepared so that a compound of the general formula III
- where in the formula the meaning of R is as defined above - is hydrogenated,
or the R4 protective group of a compound of the general formula IVb.
- where in the formula the meaning of R is as defined above and
R4 represents a protective group containing silicium atom, trityl-, methoxytntyl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or Cj-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R - is removed.
Hydrogenation of the compound of the general formula III is carried out in the presence of catalyst.
As catalyst platinum oxide, Pd/C catalyst, preferably Pd/C catalyst may be applied.
The compounds of the general formula III
are novel- where in the formula
R2 represents -(CH2)n Y, where
Y stands for hydrogen atom, halogen atom, phenyl-, -OR5 or -COOR5 group, wherein
R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(CM )alkylsilyl- or (Ci-4)alkyl-di(C6-1o)arylsilyl- group and n stands for 1,2,3,4 -, with the proviso that R5 in -COOR5 cannot stay for C alkyl.
The compounds of the general formula III can be prepared so that the R4 protective group of the compounds of the general formula IVa.
- where in the formula
R has the meaning as defined above and
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R2 - R4 is removed.
The R protective group containing the silicium atom is preferably phenyldimethylsilyl-, triethylsilyl-, triisopropylsilyl-, tert-butyldimethylsilyl- or tert-butyldiphenylsilyl- group.
Removal of the R4 protective group is carried out by methanolysis, in the presence of base.
The compounds of the general formula IV
- where in the formula
R represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(C1-4)alkyIsilyl- or (Ci-4)alkyl-di(C -1o)arylsilyl- group,
n stands for 1,2,3,4,
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R , and
the dotted line represents single or double bond - are novel compounds. The novel compounds of the general formula IVa.
- where in the formula
R represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(Cj-4)alkylsilyl- or (CM)alkyl-di(C6-io)arylsilyl- group,
n stands for 1,2,3,4, and
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R ,
can be prepared so that a compound of the general formula V
-where in the formula the meanings of R2 and R4 are as defined above - is selectively reduced.
Reduction of the compound of formula V is performed with borane compound, in the presence of oxazaborolidine catalyst.
As borane compound catecholborane, borane-diethylaniline complex, borane-dimethyl sulfide complex, preferably borane-dimethyl sulfide complex is applied.
The compounds of the general formula V are novel.
The novel compounds of the general formula V can be prepared so that a compound of the general formula Via.
CH3-(CH2)4-CO-CH2-PO(OR6)2
-where in the formula R6 represents C alkyl- or phenyl- group. The novel compounds of the general formula IVb.
-where in the formula
R2 represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means Cu alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-io)arylsilyl- group,
n stands for 1,2,3,4, and
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R2,
can be prepared so that a compound of the general formula VIb.
R2 and R4 have the meanings as defined above -, is reacted with an organic metal reagent, in the presence of chiral catalyst.
As organic metal reagent dipentylzinc or pentylmagnesium bromide, as chiral catalyst (2S)-3- exo-(morpholino)isoborneol may be applied.
The compounds of the general formulae Via. and VIb. are novel.
The compounds of the general formula VI
-where in the formula
R2 represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or
group,
n stands for 1,2,3,4,
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R2,
and x represents 0 or 2 - can be prepared so that a compound of the general formula VII
VII
-where in the formula
x, R2 and R4 have the meanings as defined above-, is oxidized.
Oxidation of the compound of formula VII is carried out with PCC (pyridinium chlorochromate) or under Swern conditions (oxalyl chloride/DMSO/organic base) or with TEMPO (2,2,6,6- tetramethyl-l-piperidinyloxy free radical), or under Pfitzner-Moffat conditions (DCC
(dicyclohexylcarbodiimide)/DMSO/acid).
The compounds of the general formula VII are novel.
The novel compounds of the general formula VII can be prepared so that the R1 protective group of a compound of the general formula VIII
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl,- ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- group, with the proviso that the R1 protective group must be selectively removable from R2 and
The protective group R1 which contains silicium atom is preferably phenyldimethylsilyl-, triethylsilyl-, triisopropylsilyl-, tert-butyldimethylsilyl- or tert-butyldiphenylsilyl- group.
The compounds of the general formula VIII are novel.
The novel compounds of the general formula VIII can be prepared so that a compound of the general formula EX.
-where in the formula
x, R1 and R2 have the meanings as defined above-, is reacted with a compound suitable for the introduction of a group R4.
As the compound suitable for the introduction of group R4 preferably p-phenylbenzoyl chloride is applied.
The compounds of the general formula IX are novel.
The novel compounds of the general formula IX can be prepared so that a compound of the general formula X
- where in the formula
x, R and R have the meanings as defined above -, is reduced.
Reduction of the compound of the general formula X can be carried out with diisobutylaluminum hydride, lithium aluminum hydride, aluminum isopropylate, or sodium borohydride, preferably sodium borohydride.
The novel compounds of the general formula X can be prepared so that a compound of the general formula XI
-where in the formula
1 9
x, R and R have the meanings as defined above,
R3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl,- ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or Ci-13 acyl- group - is catalytically hydrogenated, and
in the case where x=0 isomerized.
For the hydrogenation of the compound of formula XI as catalyst Pd/C catalyst or platinum oxide, preferably Pd/C catalyst may be used.
The compounds of the general formula XI are novel.
The novel compounds of the general formula XI can be prepared so that a compound of the general formula XII
- where in the formula
x, R1, R2 and R3 have the meanings as defined above - is subjected to intramolecular cyclisation.
For the intramolecular cyclisation favourably the Pauson-Khand cyclisation method is applied. The Pauson- Khand cyclisation is performed using dicobalt octacarbonyl.
Dicobalt octacarbonyl may be applied in equimolar, or less than equimolar or more than equimolar ratios.
The reaction is preferably performed in carbon monoxide atmosphere using ethyl acetate as solvent.
The novel compounds of the general formula XII can be prepared so that a compound of the general formula XIII
-where in the formula
x, R1 and R2 have the meanings as defined above - is reacted with a compound suitable for the introduction of group R .
The novel compounds of the general formula XIII can be prepared so that
a.) a compound of the general formula XIV
-where in the formula
x, R and R have the meanings as defined above - is selectively reduced, or b.) a compound of the general formula XVI
- where in the formula
R has the meaning as defined above -, is reacted with a compound of the general formula XVII
R1
^(CH2)x— O
XVII
- where in the formula
R1 and x have the meanings as defined above - in the presence of a chiral base and zinc salt.
Reduction of the compound of the general formula XIV is carried out with borane compound, in the presence of chiral oxazaborolidine catalyst.
As borane compound, borane-dimethyl sulfide complex, catecholborane or borane-diethylaniline complex, preferably borane-dimethyl sulfide complex, as chiral base, chiral aminoalcohols or diamines, preferably (+)-N-methylephedrine may be applied.
In the reaction of the compounds of the general formulae XVI and XVII, as zinc salt preferably zinc triflate may be applied.
The novel compounds of the general formula XIV can be prepared so that a compound of the general formula XV
- where in the formula
x, R and R have the meanings as defined above -, is oxidized.
Oxidation of the compound of formula XV is carried out with PCC (pyridinium chlorochromate) or under Swern reaction conditions (oxalyl chloride/DMSO/organic base).
The novel compounds of the general formula XV can be prepared so that a compound of the general formula XVI
- where in the formula
R has the meaning as defined above -, is reacted with a compound of the general formula XVII
XVII
- where in the formula
R1 has the meaning as defined above and x is 0 or 2 -, in the presence of Grignard reagent.
As Grignard reagent methyl-, ethyl-, propyl-, butyl-, cyclohexyl- magnesium bromide, preferably methylmagnesium bromide may be applied.
A further subject of our invention is novel method for the preparation of the amorph, anhydrate, monohydrate and polyhydrate salts of treprostinil of formula I given with bases
Treprostinil salts, among them treprostinil sodium salt, in general form are described in
W099/25357 (United Therapeutics), without characterizing them with chemical-physical date. First time in Exhibit 1 -Applicant's submission to EP 1628654 (United Therapeutics) is the melting point of treprostinil sodium salt mentioned as being 56°C.
WO 2012/088607 (Alphora) describes a new process for the preparation of treprostinil sodium salt in that treprostinil is dissolved in a water-miscible organic solvent to form treprostinil solution, than the solution is reacted with an aqueous solution containing an alkali metal cation to form a reaction mixture containing the treprostinil salt, the salt is allowed to crystallization and the salt formed is collected.
According to the present invention the amorph, anhydrate, monohydrate and polyhydrate salts of treprostinil of formula I given with bases are prepared in a way that treprostinil is dissolved in polar solvent, the solid base is added to the solution, the reaction mixture is agitated and when salt formation is completed the solution is filtered, concentrated, the solvent of the concentrate is exchanged for the organic solvent of the crystallisation and the treprostinil salt is crystallized.
To prepare the salts of treprostinil of formula I. given with bases, as polar solvent C1-5 open-chain or branched organic alcohol, preferably ethanol, as base a solvent-free organic or inorganic base which contains the cation of the desired salt, for example an organic or inorganic base containing
alkali metal cation or alkali earth-metal cation, e.g. sodium carbonate monohydrate, sodium hydrogen carbonate or sodium methylate, preferably a hydrate of sodium carbonate may be applied.
The reaction mixture is agitated in an inert atmosphere until salt formation is completed.
According to one embodiment of the invention as organic solvent of the crystallisation aqueous ether-, ester- or ketone-type solvent, i.e. as ether-type solvent an open-chain or branched simple or mixed ether, preferably tert-butyl methyl ether may be applied.
Crystallisation is preferably carried out at a temperature between 50°C - (- 40°C).
As a result of the above method using an organic or inorganic base containing sodium cation white crystalline treprostinil sodium salt monohydrate (Form A) is obtained which is a new compound.
According to an another embodiment of the invention if the organic solvent of crystallisation is a water-free ether-, ester- or ketone-type solvent, then the amorphous treprostinil sodium salt is obtained which is a new compound.
According to the invention treprostinil sodium salt anhydrate (Form B) can be prepared by carrying out the above process till the crystallisation step and performing the crystallisation at 60- 100°C or in vacuum. Another possible method is that the sodium salt monohydrate is taken up and stirred at 60-90°C for 1-6 hours in a solvent which does not, or only sparingly dissolves the salt. As solvent preferably hexane, heptane, toluene, ethyl acetate may be applied.
If treprostinil sodium salt monohydrate or the anhydrate is kept in an atmosphere of 60% moisture content for 48 hours, or on the air for 5-8 days, then the novel treprostinil sodium salt polyhydrate (Form C) is obtained.
DSC and X-ray powder diffraction (XRPD) spectra of the different forms are shown in the Figures 14-22.
These above mentioned salt forms show suitable stability and applicability for the preparation of pharmaceutical formulations.
In a preferred embodiment of the invention:
The propargyl alcohol is protected with methoxymethyl group.
The protected propargyl alcohol (XVII) is reacted with 2-allyl-3-methoxybenzaldehyde (XVI) in the presence of methylmagnesium bromide Grignard reagent. The thus obtained racemic alcohol (XV) is oxidized.
The oxidation is carried out e.g. by the Swern oxidation method or by oxidation with chromium(VI).
Stereoselective reduction of the ketone XIV results the chiral alcohol XIII.
The stereoselective reduction may be carried out e.g. with borane-dimethyl sulfide complex in the presence of Corey catalyst.
The chiral alcohol XIII may directly be prepared by reacting the protected propargyl alcohol (XVII) with 2-allyl-3-methoxybenzaldehyde (XVI) in the presence of chiral base, e.g. (+)-N- methylephedrine and zinc triflate.
The hydroxyl group is protected with tert.-butyldimethylsilyl group, the silyl ether (XII) is cyclized in Pauson-Khand reaction in the presence of dicobalt octacarbonyl. As a result of the reaction the tricycle (XI) is formed by incorporation of a CO molecule.
The cyclisation can be carried out using equimolar amount of dicobalt octacarbonyl, or more preferably with catalytic amount of dicobalt octacarbonyl under carbon monoxide atmosphere. The silyloxy group is removed by catalytic hydrogenation and the double bond of the five- membered ring is saturated. The stereostructure of the tricyclic ketone (X) is formed by isomerisation with base (diazabicyclononane/ethanol).
The oxo group is reduced (IX), the resulting secondary hydroxyl group is protected with p- phenylbenzoyl (PPB) group (VIII).
The methoxymethyl protecting group is cleaved by treatment with acid (VII).
The primary hydroxyl group is oxidized (VI).
The resulting aldehyde VI is, without isolation, reacted with 2-oxo-heptylphosphonate.
The thus obtained enone V is reduced by a selective reduction method, e.g. with borane-dimethyl sulfide complex, in the presence of Corey catalyst.
The p-phenylbenzoyl protecting group of the resulting compound of formula IV is removed by methanolysis, in the presence of base.
Saturation of the double bond of the enol of formula III by catalytic hydrogenation results the benzindene derivative of formula II.
According to another preferred embodiment of the invention 2-pent-4-ynoxytetrahydropyran is used as starting material, instead of the protected propargyl alcohol. The side-chain is built out stereoselectively in the presence of chiral catalyst, by reaction with dipentylzinc or
pentylmagnesium bromide.
The benzindene of formula II is the key-intermediate to treprostinil, it is transformed to treprostinil by known chemical steps.
The first chemical step is the cleavage of the methyl ether. Removal of the methyl group is carried out with a mercaptan, in the presence of aluminum halide.
As for aluminum halide aluminum trichloride, as for mercaptan, instead of the commonly used ethanethiol, the odourless dodecanethiol has been chosen for the preparation of the trihydroxy derivative. (Figure 10)
Figure 10
The next step is the alkylation of the aromatic hydroxyl group with a haloacetic acid ester, bromo- or chloroacetic acid ethyl- or methyl ester. In our process the trihydroxy derivative alkylated with bromoacetic acid ethyl ester. (Figure 11)
In our method the hydrolysis is carried out with aqueous sodium hydroxide solution, in tetrahydrofuran.
When the reaction is completed, the reaction mixture is washed with tert-butyl methyl ether. The pH of the aqueous phase is set to pH< 3 by addition of aqueous acid solution. Treprostinil is extracted with tert-butyl methyl ether, the product solution is washed and evaporated. (Figure 12)
Figure 12
For the salt formation, treprostinil is dissolved in ethanol and solid sodium carbonate
monohydrate is added to it. (Figure 13).
Figure 13
The solution is filtered through microfilter, the ethanol is exchanged for tert-butyl methyl ether which has been saturated with water and the treprostinil sodium salt is crystallized at room temperature.
The advantages of the method according to the invention:
The formation of the benzindene tricycle does not require expensive chiral starting material.
The construction of the side-chain is realized by well-scalable and robust chemical steps (Wittig- or modified Wittig reaction) which are used in the prostaglandin chemistry, or carried out stereoselectively by use of organic metal compound, in the presence of chiral catalyst.
The enone obtained in the Wittig reaction can be transformed into the desired enantiomer in stereoselective reaction, in a good yield.
The applied p-phenylbenzoyl group (PPB-group) is well detectable in UV.
The PPB-group enhances the crystallisation ability of the intermediates and thus helps their purification.
Figures 1, 2, 4 and 5 are demonstrated below:
Figures 1,2,4,5:
Figure 1
TBDMS = tertiary-butyldimethylsilyl PCC = pyridinium chlorochromate Corey catalyst:
Figure 5
Further details of the processes according to the invention are demonstrated by the examples, without limiting the invention to the examples.
Examples
Example 1.
la.)
Preparation of 3-(Methoxymethoxy)-l-propyne (MOM-propynol, TREPO-1)
toluene
Propargyl alcohol Dimethoxymethane TREPO-1
M=56.06 M=76.10 =100.12
CaHtO C3H8O2 C5H8O2
2.27 ml of propargyl alcohol and 8 ml of dimethoxymethane are dissolved in 8 ml of toluene. To the solution 0.66 g of p-toluenesulfonic acid and 0.33 g of lithium bromide are added. The reaction mixture is stirred at room temperature for 20 hours, washed with sodium hydrogen carbonate solution and with water. The organic phase is dried and the solution is taken into the next step without evaporation.
Yield: cca. 2 g (50 %) of product, in solution.
NMR data: (DMSO-d6), 1H NMR (500 MHz): 4.62 ppm (H-4, 2), s; 4.16 ppm (H-3, 2), d, J=2.3 Hz; 3.41 ppm (H-1, 1), t, J=2.3 Hz; 3.26 ppm (H-5, 3), s; 13C NMR (125.8 MHz): 94.15 ppm (C-4), 79.90 ppm (C-2), 76.97 ppm (C-l), 54.97 ppm (C-5), 53.60 ppm (C-3).
lb.) Preparation of l-(2-Allyl-3-methoxyphenyl)-4-methoxymethoxy-but-2-yn-l-ol (TREP-1) (non-selective alkynylation)
VPK-5 TREPO-1 TREP-1
M=176.22 M=100.12 M=276.34
C11 H12°2 C5H802 <^16^20<->4
64 g (0.64 mol) of 3-(methoxymethoxy)-l-propyne (TREPO-1) is dissolved in nitrogen atmosphere in 600 ml of water-free tetrahydrofuran and the solution is heated to 60-65°C. To the reaction mixture 220 ml of ethylmagnesium bromide solution (3M solution in diethyl ether) (0.66 mol) is added slowly. At the end of the addition the reaction mixture is heated at reflux temperature for 45 minutes then, after cooling to 0-5°C, the solution of 100 g of 2-allyl-3- methoxybenzaldehyde (VPK-5) (0.57 mol) in 100 ml of water-free tetrahydrofuran is added dropwise. The mixture is stirred at room temperature. When the reaction is completed, the mixture is cooled to 0°C and NaHS04 (sodium hydrogen sulfate) solution is added to it. After agitation the phases are separated, the aqueous layer is extracted with ethyl acetate. The united organic phase is washed with NaHC03 (sodium hydrogen carbonate) solution and dried over sodium sulfate. The drying material is filtered off, the filtrate solution is evaporated in vacuum. The crude product is taken into the next step, without purification.
Yield: 156.8 g (100 %) of light brown oil.
NMR data: (CDC13), 1H NMR (500 MHz): 7.32 ppm (H-6, 1), dd, J=7.8 Hz and 0.8 Hz; 7.24 ppm (H-5, 1), m (t), J= 7.9 Hz, 6.87 ppm (H-4, 1), d (dd), J= 7.8 Hz and -1.0 Hz; 5.98 ppm (H- 14, 1), ddt, J= 17.1 Hz, 10.2 Hz and 5.8 Hz; 5.67 ppm (H-7, 1), m (dt), J=5.4 Hz and 1.6 Hz; 4.985 ppm (H-15a, 1), dq, J=10.1 Hz and 1.6 Hz; 4.93 ppm (H-15b, 1), dq, J=17.1 Hz and 1.8 Hz; 4.69 ppm (H-ll, 2), s; 4.28 ppm (H-10, 2), d, J= 1.7 Hz; 3.82 ppm (H-16, 3), s; 3.61 ppm (H-13a, 1), ddt, J=15.7 Hz, 5.8 Hz and 1.6 Hz; 3.55 ppm (H-13b, 1), ddt, J=15.7 Hz, 5.8 Hz and 1.6 Hz; 3.36 ppm (H-12, 3), s; 2.55 ppm (OH-7, 1), d, J= 5.5 Hz; 13C NMR (125.8 MHz): 157.75 ppm (C-3), 139.93 ppm (C-l), 136.99 ppm (C-14), 127.59 ppm (C-5), 125.97 pm (C-2), 119.31 ppm (C-6), 114.89 ppm (C-l 5), 110.93 ppm (C-4), 94.93 ppm (C-ll); 86.25 ppm (C-8), 82.01 ppm (C-9), 61.98 ppm (C-7), 55.88 ppm (C-16); 55.63 ppm (C-12), 54.59 ppm (C-10), 29.53 ppm (C-l 3).
lc.) Preparation of l-(2-Allyl-3-methoxyphenyl)-4-methoxymethoxy-but-2-yn-l-one (TREP-2) lcl. Method (oxidation with PCC)
TREP-1 TREP-2
M =276.34 M=274.32
200 g of silica gel is suspended in 1.5 1 of ethyl acetate and 470 g (2.18 mol) of piridinium chlorochromate (PCC) is added to it. To the orange coloured suspension the solution of 150 g (0.54 mol) of TREP-1 in 0.5 1 of ethyl acetate is added under stirring at 25±5°C. The reaction mixture is stirred at 35±5°C. At the end of the reaction diisopropyl ether and silica gel are added to the mixture. The suspension is filtered, the solid material is washed with ethyl acetate. The liquid filtrate is evaporated in vacuum. The crude product is purified by chromatography on silica gel using hexane: ethyl acetate eluent.
Yield: 88.1 g (59.2 %) of light brown oil.
Ic2. Method (Swem oxidation)
TREP-1 TREP-2
M=276.34 M=274.32
C16H20°4 C16H18°4
93 ml of oxalyl chloride is dissolved in 1.7 1 of dichloromethane and reacted at
-75/-85°C with 148 ml of dimethyl sulfoxide (DMSO). To the mixture 179 g of
TREP-1 is added at -75Λ85 °C. After 1 hour of stirring the reaction mixture is quenched with 621 ml of triethylamine and NaHS04 solution. The organic phase is extracted with
dichloromethane, the united organic phase is washed with 1M NaHC03 solution. The crude product is purified by chromatography on silica gel.
Yield: 140 g (79 %) of light brown oil.
NMR data: (CDC13), 1H NMR (500 MHz): 7.75 ppm (H-6, 1), dd, J=7.8 Hz and 0.9 Hz; 7.305 ppm (H-5, 1), t, J=8.0 Hz; 7.08 ppm, (H-4, 1), d (dd), J=8.1 Hz and -1.0 Hz; 5.96 ppm (H-14, 1), ddt, J=17.1 Hz, 10.1 Hz and 6.2 Hz; 5.01-4.92 ppm (H-15, 2), m (in: 4.98 ppm (H-15b, 1), dq, J=17.2 Hz and 1.7 Hz and 4.94 ppm (H-15a, 1), dq, J=10.1 Hz and 1.6 Hz); 4.745 ppm (H-11, 2), s; 4.45 ppm (H-10, 2), s; 3.85 ppm (H-16, 3), s; 3.78 ppm (H-13, 2), dt, J=6.2 Hz and 1.5 Hz; 3.40 ppm (H-12, 3), s; 13C NMR (125.8 MHz): 179.21 ppm (C-7), 158.21 ppm (C-3), 136.66 ppm (C-14); 133.60 ppm (C-1); 130.29 ppm (C-2), 126.98 ppm (C-5), 124.98 ppm (C-6), 115.42 ppm (C-4), 114.93 ppm (C-15), 95.38 ppm (C-ll), 88.69 ppm (C-9), 85.73 ppm (C-8), 56.16 ppm (C-16), 55.87 ppm (C-12), 54.32 ppm (C-10), 29.78 ppm (C-13).
Id.) Preparation of (lS)-l-(2-allyl-3-methoxyphenyl)-4-(methoxymethoxy)but-2-yn-l-ol
(TREP-3) ldl. Method (selective reduction)
TREP-2 TREP-3
M=274.32 M=276.34
In 600 ml of water-free tetrahydrofuran (THF) under nitrogen atmosphere 85 g of TREP-2 (0.31 mol) is dissolved. The solution is cooled to 0-5°C and 370 ml (0.37 mol) of oxazaborolidine solution (1M solution in toluene) is added to it. The mixture is cooled to (-30)°C and 50 ml (0.52
mol) of borane-dimethyl sulfide complex is added to it dropwise at (-30)°C. The reaction mixture is stirred at that temperature. At the end of the reaction the mixture is allowed to warm up to (- 15) °C, 200 ml of methanol is carefully added (strong foaming and heat formation). After the methanol addition the reaction mixture is stirred for 30 minutes, then NH4C1 solution is added at 0-5°C and the quenched reaction mixture is extracted with 3 x 2.5 1 of ethyl acetate. The united organic phase is washed with water and dried over sodium sulfate. The drying material is filtered off, the filtrate is evaporated.
Yield: 85.6 g (100 %) of light brown oil.
Id2. Method (selective alkynylation)
VPK-5 TREPO-1 TREP-3
M=176.22 M=100.12 M=276.34
CiiH,202 C5He02 CieH2o04
The reaction vessel is charged with 216 mg (0.59 mmol) of zinc triflate and 82 mg (0.45 mmol) of (+)-N-methylephedrine, flushed with nitrogen gas for 10 minutes, then 1 ml of dist. toluene and 63 microl (0.45 mmol) of triethylamine are added. The reaction mixture is stirred at room temperature for 1 hour, then 250 microl (0.45 mmol) of TREPO-1 solution and after 15 minutes of stirring 24 microl of VPK-5 (2-allyl-3-methoxybenzaldehyde) (0.14 mmol) are added. Following 24 hours of stirring at room temperature, the reaction mixture is quenched with 1 ml of saturated NH4CI solution. The aqueous phase is extracted with toluene, the united organic phase is washed consecutively with NaHC03 solution and saturated NaCl solution, then evaporated.
Yield: 30 mg (78%) of light brown oil.
NMR data: (CDC13), 1H NMR (500 MHz): 7.32 ppm (H-6, 1), dd, J=7.8 Hz and 0.9 Hz; 7.25 ppm (H-5, 1), m (t), J= 8.0 Hz, 6.875 ppm (H-4, 1), d (dd), J- 7.8 Hz and -1.0 Hz; 5.98 ppm (H- 14, 1), ddt, J= 17.1 Hz, 10.2 Hz and 5.8 Hz; 5.68 ppm (H-7, 1), broad; 4.99 ppm (H-15a, 1), dq,
J=10.1 Hz and 1.6 Hz; 4.93 ppm (H-15b, 1), dq, J=\7A Hz and 1.8 Hz; 4.70 ppm (H-11, 2), s; 4.285 ppm (H-10, 2), d, J= 1.8 Hz; 3.82 ppm (H-16, 3), s; 3.62 ppm (H-13a, 1), ddt, J=15.7 Hz, 5.8 Hz and 1.6 Hz; 3.545 ppm (H-13b, 1), ddt, J=15.7 Hz, 5.8 Hz and 1.6 Hz; 3.36 ppm (H-12, 3), s; 2.34 ppm (OH-7, 1), broad; 13C NMR (125.8 MHz): 157.79 ppm (C-3), 139.90 ppm (C-l), 137.06 ppm (C-14), 127.67 ppm (C-5), 125.99 pm (C-2), 119.35 ppm (C-6), 114.96 ppm (C-15), 110.98 ppm (C-4), 94.99 ppm (C-l l); 86.18 ppm (C-8), 82.13 ppm (C-9), 62.10 ppm (C-7), 55.93 ppm (C-16); 55.70 ppm (C-12), 54.62 ppm (C-10), 29.57 ppm (C-13).
le.) Preparation of [(lS)-l-(2-Allyl-3-methoxyphenyl)-4-(methoxymethoxy)but-2-ynoxy]-tert- butyldimethylsilane (TREP-4)
TREP-3 TREP-4
M=276.34 M=390.60
C16H20O4 C22H34O4S1
In 850 ml of toluene are dissolved 85 g (0.31 mol) of TREP-3 and 26.6 g (0.39 mol) of imidazole. The solution is cooled to 5-10°C and 56.8 g (0.38 mol) of tert-butyldimethylsilyl chloride (TBDMSCI) is added. The reaction mixture is stirred at room temperature for 4 hours, then 500 ml of water is added under agitation. The phases are separated, the aqueous layer is extracted with toluene, the united organic phase is evaporated in vacuum. The crude product is chromatographed on silica gel using hexane: ethyl acetate eluent.
Yield: 104.2 g (86.7 %) of light brown oil.
NMR data: (CDC13), 1H NMR (500 MHz): 7.27 ppm (H-6, 1), m (dd), J=7.9 Hz and 1.1 Hz, 7.225 ppm (H-5, 1), t, J=7.9 Hz; 6.83 ppm (H-4, 1), dd, J=7.9 Hz and 1.0 Hz; 5.95 ppm (H-14, 1), dddd, J=17.0 Hz, 10.3 Hz, 6.5 Hz and 5.3 Hz; 5.64 ppm (H-7, 1), t, J=1.5 Hz; 5.00-4.91 ppm (H-15, 2), m ( 4.98 ppm (H-15a, 1), dq, J=10.1 Hz and 1.6 Hz; 4.94 ppm (H-15b, 1), dq, J=17.1 Hz and 1.8 Hz); 4.67 ppm (H-11, 2), s; 4.22 ppm (H-10, 2), m; 3.82 ppm (H-16, 3); s; 3.62 ppm (H-13a, 1), ddt, J=15.7 Hz, 5.1 Hz and 1.9 Hz; 3.49 ppm (H-13b, 1), ddt, J=15.7 Hz, 6.5 Hz and
1.5 Hz; 3.34 ppm (H-12, 3), s; 0.91 ppm (H-20, H-21 and H-22, 9), s; 0.13 ppm, (H-17/H-18, 3), s; 0.085 (H-18/H-17, 3), s; 13C NMR (125.8 MHz): 157.50 ppm (C-3), 141.44 ppm (C-l), 136.55 (C-14), 127.32 (C-5), 124.78 ppm (C-2), 118.73 ppm (C-6), 114.71 ppm (C-15), 110.10 ppm (C-4), 94.80 ppm (C-ll), 87.16 (C-8), 80.71 ppm (C-9), 62.27 ppm (C-7), 55.82 ppm (C- 16), 55.63 (C-12), 54.60 ppm (C-10), 29.59 ppm (C-13), 25.93 ppm (C-20, C-21 and C-22), 18.40 ppm (C-19), -4.45 ppm (C-17/C-18), -4.74 ppm (C-18/C-17).
If.) Preparation of (3aS,9R)-9-[tert-butyl(dimemyl)silyl]oxy-5-methoxy-l- (methoxymethoxymethyl)-3,3a,4,9-tetrahydrocyclopenta[b]naphthalen-2-one
TREP-4 TREP-5
M=390.60 M=4 8.61
C23H 3 06Si
lfl. Method (with 100 mol% of dicobalt octacarbonyl)
93 g (0.24 mol) of TREP-4 is dissolved under nitrogen atmosphere in 930 ml of ethyl acetate and to the solution 85.5 g (0.25 mol) of dicobalt octacarbonyl is added. The reaction mixture is stirred at room temperature for 2.5 hours and then warmed to 60-70°C. The evolving carbon monoxide gas is lead away in closed system. At the end of the reaction the mixture is cooled to room temperature and air is bubbled through for 12 hours. The reaction mixture is filtered, the precipitate is washed with ethyl acetate. The united filtrate solution is evaporated in vacuum. The crude product is chromatographed on silica gel using hexane: ethyl acetate eluent.
Yield: 64.6 g (64.8%) of light brown oil.
1£2. Method (with 10 mol% dicobalt octacarbonyl + carbon monoxide gas)
93 g (0.24 mol) of TREP-4 is dissolved in 930 ml of ethyl acetate under nitrogen atmosphere and 8.55 g (0.025 mol) of dicobalt octacarbonyl is added to it. The vessel is flushed with carbon monoxide, the reaction mixture is stirred at room temperature for 2.5 hours and then heated to 60-70°C. At the end of the reaction the mixture is cooled to room temperature, filtered, the precipitate is washed with ethyl acetate. The united filtrate solution is evaporated in vacuum. The crude product is chromatographed on silica gel using hexane: ethyl acetate eluent.
Yield: 85 g (85 %) of light brown oil.
NMR data: (CDC13), 1H NMR (500 MHz): 7.24 ppm (H-22, 1), m (t), J=8.0-7.4 Hz, 6.92 ppm (H-23, 1), d, J=7.3 Hz; 6.79 ppm (H-21, 1), d, J=7.8 Hz; 5.775 ppm (H-7, 1), s; 4.68-.453 ppm (H-15, 2), m, (in: 4.62 ppm (H-15a, 1), d, J=5.6 Hz and 4.59 ppm (H-15b, 1), d, J=5.6 Hz); 4.30 ppm (H-13, 2), m; 3.815 ppm (H-2, 3), s; 3.55 ppm (H-4a, 1), dd, J=16.9 Hz and 7.3 Hz; 3.45 ppm (H-9, 1), m (ddd), J-7.8-7.0 Hz; 3.33 ppm (H-17, 3), s; 2.75 ppm (H-lOa, 1), dd, J=18.7 Hz and 5.8 Hz; 2.33-2.15 ppm (H-lOb and H-4b, 2), m, (in: 2.27 ppm (H-lOb, 1), d, J-19.5 Hz and 2.22 ppm (H-4b, 1), dd, J=16.8 Hz and 10.2 Hz); 0.82 ppm (H-27, H-28 and H-29, 9), s; 0.15 ppm (H-24/H-25, 3), s; 0.10 ppm (H-24/H-25, 3), s; 13C NMR (125.8 MHz): 208.44 ppm (C- 11), 176.76 ppm (C-8), 156.93 ppm (C-3), 138.31 ppm (C-6), 132.99 ppm (C-12), 127.61 ppm (C-22), 124.88 ppm (C-5), 122.07 ppm (C-23), 109.41 ppm (C-21), 96.42 ppm (C-15), 65.25 ppm (C-7), 59.07 ppm (C-13), 55.55 ppm (C-17), 55.47 ppm (C-2), 42.32 ppm (C-10), 33.49 ppm (C-4), 32.61 ppm (C-9), 25.75 ppm (C-27, C-28 and C-29), 18.20 ppm (C-26), -4.19 ppm (C-24/C-25), -4.32 ppm (C-25/C-24). lg.) Preparation of (lS,9aS)-5-methoxy-l-(methoxymethoxymethyl)-l,3,3a,4,9,9a- hexahydrocyclopenta[b]naphthalen-2-one (TREP-6)
TREP-5 TREP-6
63 g (0.15 mol) of TREP-5 is dissolved in 630 ml of ethyl acetate and 19 ml of pyridine is added
to the solution. The reaction mixture is hydrogenated over 25 g of 10% palladium on charcoal catalyst under 6 bar pressure. At the end of the reaction the catalyst is filtered off and washed with ethyl acetate. The filtrate is evaporated in vacuum. The crude product is chromatographed on silica gel using hexane: ethyl acetate mixture as eluent. The evaporated main fraction is crystallized at 0°C from hexane-ethyl acetate mixture and collected by filtration. The evaporated mother liquor is, in order of isomerisation, dissolved in the mixture 100 ml of toluene and 60 ml of ethanol. 12 ml of DBN reagent (2,3,4,6,7,8-hexahydropyrrolo[l,2-a]pyrimidine) is added to it at 0°C and the mixture is agitated for 15 minutes. The reaction mixture is then quenched with NaHS04 solution, extracted with tert-butyl methyl ether and evaporated. The residue is chromatographed on silica gel using hexane:ethyl acetate mixture as eluent. The evaporated main fraction is crystallized at 0°C from hexane-ethyl acetate mixture. The crystals are collected by filtration and united with earlier gained crystals.
Yield: 30.2 g (69.1 %) of white crystals. Mp: 65-67 °C.
NMR data: (CDC13), 1H NMR (500 MHz): 7.13 ppm (H-22, 1), m (t), J=7.9 Hz, 6.78 ppm (H- 23, 1), d, J=7.6 Hz; 6.71 ppm (H-21, 1), d, J=8.2 Hz; 4.62-4.56 ppm (H-15, 2), m, (in: 4.60 ppm (H-15a, 1), d, J=6.5 Hz and 4.58 ppm (H-15b, 1), d, J=6.5 Hz); 3.86 ppm (H-13a, 1), dd, J= 9.8 Hz and 4.2 Hz; 3.81 ppm (H-2, 3), s; 3.67 ppm (H-13b, 1), m (dd), J=9.8 Hz and 3.6 Hz, 3.35 ppm (H-17, 3), s; 3.09 ppm (H-7a, 1), dd, J=16.6 Hz and 6.5 Hz; 3.03 ppm (H-4a, 1), dd, J=17.3 Hz and 7.1 Hz, 2.82 ppm (H-7b, 1), m (dd), J=16.6 Hz and 3.6 Hz, 2.715 ppm (H-8, 1), m (dtd), J=10.3 Hz, 6.8 Hz and 3.7 Hz, 2.605 ppm (H-9, 1), m (dqd), J-8.7 Hz, -7.3 Hz and 3.1 Hz; 2.47 ppm (H-lOa, 1), m (dd), J=18.1 Hz and 7.6 Hz, 2.29-2.205 ppm (H-4b and H-lOb, 2), m; 2.07 ppm (H-12, 1), m (ddd), J=10.5 Hz and -3.6 Hz; 13C NMR (125.8 MHz): 218.28 ppm (C-11), 156.96 ppm (C-3), 136.27 ppm (C-6), 126.58 ppm (C-22), 124.50 ppm (C-5), 121.34 ppm (C- 23), 107.60 ppm (C-21), 96.65 ppm (C-15), 64.64 ppm (C-13), 55.40 ppm (C-2), 55.31 ppm (C- 17), 51.68 ppm (C-12), 46.46 ppm (C-10), 35.99 ppm (C-8), 31.06 ppm (C-7), 30.61 ppm (C-9), 25.59 ppm (C-4).
lh.) Preparation of (lS,2R,9aS)-5-methoxy-l-(methoxymethoxymethyl)-2,3,3a,4,9,9a- hexahydro- 1 H-cyclopenta[b]naphthalen-2-ol (TREP-7)
22 g (75.8 mmol) TREP-6 is dissolved in 100 ml of toluene, 100 ml of ethanol is added to it and the solution is cooled to (-)15-(-)25°C. To the solution 3 g (79.3 mmol) of sodium borohydride (NaBtL is added and the reaction mixture is stirred while keeping the above temperature. At the end of the reaction the pH is set to pH=4-6 with NaHS04 solution. Stirring is continued for 30 minutes, then the phases are separated. The aqueous phase is extracted with toluene. The united organic phase is washed consecutively with NaHC03 solution and water, then dried over sodium sulfate. The drying material is filtered off, the filtrate solution is evaporated in vacuum.
Yield: 22.15 g (100 %) of colourless oil.
NMR data: (CDC13), 1H NMR (500 MHz): 7.10 ppm (H-22, 1), t, J=7.8 Hz; 6.79-6.73 ppm (H- 21 and H-22, 2), m (in: 6.765 ppm (H-23, 1), d, J=7.3 Hz and 6.76 ppm (H-21, 1), d, J=8.2 Hz); 4.64 ppm (H-15, 2), s; 3.91 ppm (H-ll, 1), td, J=9.8 Hz and 6.4 Hz; 3.83-3.74 ppm (H-2 and H- 13a, 4), m (in: 3.81 ppm (H-2, 3), s and 3.80 ppm (H-13a, 1), dd, J=9.2 Hz and 4.7 Hz); 3.59 ppm (H-13b, 1), t (dd), J=9.0 Hz; 3.38 ppm (H-17, 3), s; 2.79-2.69 ppm (H-4a and H-7a, 2), m (in: 2.76 ppm (H-4a, 1), dd, J=14.7 Hz and 6.2 Hz and 2.72 ppm (H-7a, 1), dd, J=14.2 Hz and 6.2 Hz); 2.61-2.53 ppm (H-4b and OH-11, 2), m (in: 2.58 ppm (OH-11, 1), broad and 2.56 ppm (H-4b, 1), dd, J=14.7 Hz and 6.2 Hz); 2.45 ppm (H-7b, 1), dd, J=14.3 Hz and 6.2 Hz; 2.31 ppm (H-9, 1), m (tdt), J=10.6 Hz, 7.4 Hz and 6.3 Hz; 2.20 ppm (H-lOa, 1), ddd, J=12.0 Hz, 7.3 Hz and 6.4 Hz; 1.96 ppm (H-8, 1), tt, J=10.4 Hz and 6.1 Hz; 1.60 ppm (H-12, 1), qd/dddd, J=9.2 Hz and 4.8 Hz; 1.20 ppm (H-lOb, 1), dt, J=11.9 Hz and 10.5 Hz; 13C NMR (125.8 MHz): 156.72 ppm (C-3), 140.18 ppm (C-6), 126.89 (C-5), 126.34 ppm (C-22), 120.60 ppm (C-23), 108.64 ppm (21), 96.73 ppm (C-15), 76.30 ppm (C-11), 70.75 ppm (C-13), 55.69 ppm (C-2), 55.43 ppm (C-17), 51.91 ppm (C-12), 40.45 ppm (C-10), 37.82 ppm (C-8), 33.37 ppm (C-7), 33.20 ppm (C- 9), 25.62 ppm (C-4).
1 i.) Preparation of [(1 S,2R,9aS)-5-methoxy-l -(methoxymethoxymethyl)-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate (TREP-8)
TREP-7 TREP-8
M=292.38 M=472.59
C17H2404 C30H32O5
22 g (75 mmol) of TREP-7 is dissolved in 50 ml of pyridine under nitrogen atmosphere and 17.9 g (82 mmol) of p-phenylbenzoyl chloride (PPB-CI) is added to it at a temperature of max. 50°C. The reaction mixture is stirred at 50-60°C. At the end of the reaction ethanol and water are added and the mixture is cooled to 0/5°C-ra. After 3 hours of stirring the crystals are filtered off and washed with ethanol-water mixture.
Yield: 34.1 g (96 %) of white crystals. Mp: 106-107 °C.
NMR data: (CDC13), 1H NMR (500 MHz): 8.06 ppm (H-26 and H-26', 2), m (d), J=8.5 Hz; 7.65-7.59 ppm (H-27, H-27', H-30 and H-30', 4), m, (in: 7.63 ppm (H-27 and H-27', 2), m (d), J=8.5 Hz and 7.61 ppm (H-30 and H-30', 2), m (d), J-7.5 Hz); 7.47 ppm (H-31 and H-31 ', 2), m (t), J-7.5 Hz; 7.39 ppm (H-32, 1), m (t/tt), J=7.4 Hz; 7.15 ppm (H-22, 1), t, J=7.8 Hz; 6.83 ppm (H-23, 1), d, J=7.5 Hz; 6.79 ppm (H-21, 1), d, J=8.1 Hz; 5.23 ppm (H-11, 1), td, J=8.7 Hz and 6.2 Hz; 4.64 ppm (H-15, 2), m (s); 3.83 ppm (H-2, 3), s; 3.72-3.63 ppm (H-13, 2), m (in: 3.69 ppm (H-13a, 1), dd, J=9.9 Hz and 4.8 Hz and 3.66 ppm (H-13b, 1), dd, J=9.9 Hz and 5.3 Hz); 3.35 ppm (H-17, 3), s; 2.87 ppm (H-4a and H-7a, 2), m (dd), J=14.7 Hz and 6.1 Hz; 2.68-2.58 ppm (H-4b and H-7b, 2), m (in: 2.65 ppm (H-7b, 1), dd, J=15.1 Hz and 6.3 Hz and 2.62 ppm (H- 4b, 1), dd, J=15.5 Hz and 6.2 Hz); 2.53-2.40 ppm (H-9 and H-lOa, 2), m (in: 2.475 ppm (H-lOa, 1), m and 2.465 ppm (H-9, 1), m); 2.305 ppm (H-8, 1), m (tt), J=9.4 Hz and 6.3 Hz; 2.01 ppm (H-12, 1), m (tt), J=8.9 Hz and 4.9 Hz; 1.41 ppm (H-lOb, 1), m; 13C NMR (125.8 MHz): 166.40 ppm (C-24), 156.74 ppm (C-3), 145.65 ppm (C-28), 140.18 ppm (C-29), 140.03 ppm (C-6), 130.20 ppm (C-26 and C-26', 2), 129.35 ppm (C-25), 129.03 ppm (C-31 and C-31', 2), 128.22
ppm (C-32), 127.39 ppm (C-30 and C-30', 2), 127.10 ppm (C-27 and C-27', 2), 126.69 (C-5), 126.38 ppm (C-22), 120.71 ppm (C-23), 108.46 ppm (21), 96.72 ppm (C-15), 76.16 ppm (C-11), 67.41 ppm (C-13), 55.65 ppm (C-2), 55.32 ppm (C-17), 50.16 ppm (C-12), 37.93 ppm (C-10), 37.55 ppm (C-8), 33.70 ppm (C-9), 33.28 ppm (C-7), 25.72 ppm (C-4).
1 j .) Preparation of [( 1 S,2R,9aS)- 1 -(hydroxymethyl)-5-methoxy-2,3,3a,4,9,9a-hexahydro- 1 H- cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate (TREP-9)
TREP-8 TREP-9
28 g (59.2 mmol) of TREP-8 is dissolved in 140 ml of tetrahydrofuran and to the solution 280 ml of methanol is added.
In Method lil . 140 ml of 5 M hydrochloric acid is added to the mixture and stirred at 45-50°C. In Method li2. 14 g of p-toluene sulfonic acid monohydrate is added to the mixture and stirred at 45-50°C.
At the end of the reaction the mixture is neutralized with NaHC03 solution, the organic solvents are distilled off. The residue is extracted with ethyl acetate, the united organic phase is washed with water, dried over sodium sulfate. The crude product is chromatographed on silica gel, using hexane: ethyl acetate mixture as eluent.
Yield: 23.4 g (92 %) of colourless oil.
NMR data: (CDC13), 1H NMR (500 MHz): 8.05 ppm (H-26 and H-26', 2), m (d), J=8.5 Hz; 7.65-7.58 ppm (H-27, H-27', H-30 and H-30', 4), m, (in: 7.63 ppm (H-27 and H-27', 2), m (d), J=8.5 Hz and 7.60 ppm (H-30 and H-30', 2), m (d), J-7.4 Hz); 7.46 ppm (H-31 and H-31 ', 2), m (t), J-7.5 Hz; 7.39 ppm (H-32, 1), m (t/tt), J=7.3 Hz; 7.14 ppm (H-22, 1), t, J=7.8 Hz; 6.82-6.76 ppm (H-21 and H-23, 2), m (in: 6.792 ppm (H-23, 1), d, J-7.3 Hz and 6.788 ppm (H-21, 1), d,
J-8.4 Hz); 5.21 ppm (H-l l, 1), td, J=9.3 Hz and 6.5 Hz; 3.84 ppm (H-2, 3), s; 3.71 ppm (H-13, 2), m; 2.86-2.76 ppm (H-4a and H-7a, 2), m (in: 2.82 ppm (H-7a, 1), dd, J=14.6 Hz and 6.3 Hz and 2.80 ppm (H-4a, 1), dd, J=15.0 Hz and 6.2 Hz); 2.73-2.64 ppm (H-4b and OH-13, 2), m (in:
2.70 ppm (H-4b, 1), dd, J=15.1 Hz and 5.8 Hz and 2.67 ppm (OH-13, 1), broad); 2.56 ppm (H- 7b, 1), dd, J=14.6 Hz and 5.6 Hz; 2.45 ppm (H-9, 1), m; 2.40-2.31 ppm (H-8 and H-lOa, 2), m (in: 2.365 ppm (H-lOa, 1), m, J-11.9 and 7.0 and 2.35 ppm (H-8, 1), m, J=10.4 Hz and 7.1 Hz);
1.71 ppm (H-12, 1), m tt, J=9.2 Hz and 4.1 Hz; 1.53 ppm (H-lOb, 1), dt, J=12.1 Hz and 9.5 Hz; 13C NMR (125.8 MHz): 167.40 ppm (C-24), 156.86 ppm (C-3), 146.01 ppm (C-28), 140.08 ppm (C-29), 139.79 ppm (C-6), 130.34 ppm (C-26 and C-26', 2), 129.06 ppm (C-31 and C-31 ', 2), 128.83 ppm (C-25), 128.32 ppm (C-32), 127.41 ppm (C-30 and C-30', 2), 127.16 ppm (C-27 and C-27', 2), 126.51 (C-5), 126.42 ppm (C-22), 120.88 ppm (C-23), 108.52 ppm (C-21), 75.40 ppm (C-l l), 61.16 ppm (C-13), 55.69 ppm (C-2), 52.83 ppm (C-12), 37.56 ppm (C-10), 36.32 ppm (C-8), 33.01 ppm (C-9), 32.71 ppm (C-7), 25.48 ppm (C-4).
Ik.) Preparation of [(lR,2R,3aS,9aS)-5-methoxy-l-[(E)-3-oxooct-l-enyl]-2,3,3a,4,9,9a- hexahydro- 1 H-cyclopenta[b]naphthalen-2-yl] 4-phenylbenzoate (TREP-11)
TREP-9 TREP-10 TREP-11
M=426.52 M=522.69
M=428.53
C28H2604 C^O,,
^28^28¾
20 g (46.7 mmol) of TREP-9 is dissolved in an inert atmosphere in 200 ml water-free toluene. 30 g of dicyclohexylcarbodiimide (DCC) and 10 ml of dimethyl sulfoxide in phosphoric acid are added. The reaction mixture is heated to 50°C and in portions, a further 5 ml of dimethyl sulfoxide in phosphoric acid are added. When the oxidation is completed, the reaction mixture is cooled to -10°C and at that temperature 4 g (71 mmol) of potassium hydroxide and then 10.9 g (49 mmol) of 2-oxo-heptylphosphoric acid dimethyl ester in toluene solution are added. At the end of the reaction, under agitation, the mixture is poured onto acid solution. The precipitated crystals are filtered off and washed. The phases of the filtrate are separated, the organic phase is washed with 1M sodium hydrogen carbonate solution and then with diluted hydrochloric acid
solution. The organic phase is evaporated and purified by chromatography on silica gel column using toluene: hexane eluent.
Yield: 23 g (94,3 %) of light brown oil.
Alternative method of lk/2
20 g(46,7mmol) of TREP-9 is dissolved in 200ml toluene and 0,9 g potassium bromide and 0,2 g TEMPO/(2,2,6,6-Tetramethyl- piperidin-l-yl)oxyl / catalyst are added to the solution. The reaction mixture is cooled to the range of 0 C- (+10 C) and 150ml sodium hypochlorite solution are added(active chlorine content is 6-14%) and the mixture is stirred at this temperature. When the oxidation is completed the phases of the reaction mixture are separated, organic phase is washed with aqueous solution of Na2S203 , with aqueous solution of KBr and finally with water.
10,9 g (49mmol) 2-oxo-heptylphosphoric acid dimethyl ester and 100 ml 3 M potassium hydroxide solution are added to the organic phase. The reaction mixture is agitated at room temperature. After completion of the reaction the phases are separated and the organic phase is washed with 1 M sodium hydrogen sulfate solution and 15% NaCl solution.
The organic phase is evaporated and purified by chromatography on silica gel column using toluene :hexane eluent.
Yield: 23 g (94,35%) of light brown oil.
NMR data: (CDC13), 1H NMR (500 MHz): 8.00 ppm (H-26 and H-26', 2), m (d), J=8.3 Hz; 7.64-7.56 ppm (H-27, H-27', H-30 and H-30', 4), m, (in: 7.61 ppm (H-27 and H-27', 2), m (d), J=8.4 Hz and 7.59 ppm (H-30 and H-30', 2), m (d), J-7.7 Hz); 7.45 ppm (H-31 and H-31', 2), m (t), J-7.5 Hz; 7.38 ppm (H-32, 1), m (t tt), J=7.3 Hz; 7.165 ppm (H-22, 1), t, J=7.9 Hz; 6.83-6.76 ppm (H-13, H-21 and H-23, 3), m (in: 6.80 ppm (H-21 and H-23, 2), d, J=7.9 Hz and 6.80 ppm (H-13, 1), dd, J=15.8 Hz and 8.3 Hz); 6.12 ppm (H-14, 1), d, J=15.8 Hz; 5.18 ppm (H-ll, 1), td, J=9.6 Hz and 6.2 Hz; 3.83 ppm (H-2, 3), m (s); 2.79-2.70 ppm (H-4 and H-7a, 3), m (in: 2.75 ppm (H-7a, 1), dd, J=14.7 Hz and 5.9 Hz and 2.73 ppm (H-4, 2), d, J=5.5 Hz); 2.62-2.48 ppm (H-7b, H-9, H-lOa and H-16, 5), m (in: 2.565 ppm (H-9, 1), m; 2.55 ppm (H-16, 1), t, J=7.4 Hz; 2.53 ppm (H-lOa, 1), m; 2.515 ppm (H-7b, 1), m); 2.40-2.27 ppm (H-8 and H-12, 2), m (in: 2.36 ppm (H-12, 1), m and 2.31 ppm (H-8, 1), m); 1.67-1.53 ppm (H-17, 2), m (tt), J=7.4 Hz, 1.38- 1.22 ppm (H-lOb, H-18 and H-19, 5), m (in: 1.34 ppm (H-lOb, 1), m (dt), J-11.8 Hz and 9.6 Hz; 1.29 ppm (H-19, 2) m and 1.28 ppm (H-18, 2) m); 0.87 ppm (H-20, 3), m (t), J=6.9 Hz; 13C
NMR (125.8 MHz): 200.85ppm (C-15), 166.23 ppm (C-24), 156.99 ppm (C-3), 146.53 ppm (C- 13), 145.89 ppm (C-28), 140.14 ppm (C-29), 139.28 ppm (C-6), 131.85 ppm (C-14), 130.22 ppm (C-26 and C-26', 2), 129.05 ppm (C-31 and C-31 ', 2), 128.93 ppm (C-25), 128.28 ppm (C-32), 127.41 ppm (C-30 and C-31 ', 2), 127.14 ppm (C-27 and C-27', 2), 126.70 (C-22), 126.23 ppm (C-5), 120.93 ppm (C-23), 108.76 ppm (C-21), 77.31 ppm (C-11), 55.69 ppm (C-2), 53.49 ppm (C-12), 40.24 ppm (C-8), 40.16 ppm (C-16), 37.89 ppm (C-10), 33.16 ppm (C-9), 31.88 ppm (C- 7), 31.58 ppm (C-18), 25.32 ppm (C-4), 24.08 ppm (C-17), 22.60 ppm (C-19), 14.05 ppm (C- 20).
Preparation of 2-Oxo-heptylphosphonic acid dimethyl ester
Methyl hexanoate Heptylphosphonate
Caproic acid methyl ester 2-Oxo-heptylphosphonic acid dimethyl ester
M=130.19 M=222.22
C7H14O2 C9H19O4P
Preparation of lithium diisopropylamide ( LDA)
In nitrogen atmosphere, under stirring 3.017 g of diisopropylamine is dissolved in 13.6 ml of tetrahydrofuran (THF) and to it is added at 0±5°C the hexane solution of 17.9 ml butyl lithium (BuLi) (1.6M solution in hexane). The mixture is stirred for 1 hour at room temperature.
Phosphonate formation
Under nitrogen atmosphere 1.85 g of dimethyl methylphosphonate and 1.77 ml of methyl hexanoate are dissolved in 10.2 ml of tetrahydrofuran (THF), under stirring. The solution is cooled to 0/-5°C and at that temperature in a period of approx. 30 minutes the lithium
diisopropylamide (LDA) solution is added dropwise. The reaction mixture is stirred at 0/-5°C for 1 hour and then 37 ml of 2 M NaHC03 solution is added. Stirring is continued at room
temperature for lhour, the phases are separated, the aqueous phase is extracted with tert-butyl
methyl ether (TBME). The united organic phase is washed with saturated sodium chloride solution, evaporated in vacuum and dried by distilling toluene over it in rotadest on a water bath of45±5°C.
Yield: 2.718 g (90%) of yellow oil.
NMR data: (DMSO), 1H NMR (500 MHz): 3.65 ppm (H-9 and H-10, 6), d, J=11.2 Hz; 3.26 ppm (H-l, 2), m (d), J=22.1 Hz, 2.555 ppm (H-3, 2), t, J=7.2 Hz; 1.45 ppm (H-4, 2), qui (tt), J=7.3 Hz; 1.32-1.15 ppm (H-5 and H-6, 4), m, (in: 1.26 ppm (H-6, 2), m and 1.20 ppm (H-5, 2), m); 0.85 ppm (H-7, 3), t, J=7.2 Hz; 13C NMR (125.8 MHz): 202.23 ppm (C-2), d, J=5.9 Hz; 52.47 ppm (C-9 and C-10, 2), d, J=6.3 Hz; 43.04 ppm (C-3), d, J=1.4 Hz; 40.21 ppm (C-l), d, J=125.5 Hz, 30.50 ppm (C-5); 22.40 ppm (C-4); 21.82 ppm (C-6), 13.72 ppm (C-7); 31P NMR (202.46 MHz): 23.52 ppm (P-8), m.
11.) Preparation of [(lR,2R,3aS,9aS)-l-[(E,3S)-3-hydroxyoct-l-enyl]-5-methoxy-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphth-2-yl] 4-phenylbenzoate (TREP-12)
M=522.69 M=524.71
C35H40°4
19 g (36.3 mmol) of TREP-11 is dissolved under nitrogen atmosphere in 190 ml water-free tetrahydrofuran. The solution is cooled to 0-5°C and 36.3 ml (36.3 mmol) of oxazaborolidine solution (1M toluene solution) is added. The mixture is cooled to
(-30)°C and while keeping that temperature, 9.5 ml (99 mmol) of borane-dimethyl sulfide complex is added to it dropwise. The reaction mixture is stirred at that temperature. At the end of the reaction the mixture is allowed to warm to (-15)°C and carefully methanol is added to it (strong foaming and heat formation). The mixture is stirred for 30 minutes and then NaHS04
solution is added to it at 0-5°C. The precipitated crystals are filtered off and washed with toluene. The liquid filtrate is extracted with 3 x 50 ml of toluene. The united organic phase is washed with water and dried over sodium sulfate. The drying material is filtered off and the filtrate is evaporated.
Yield: 18.2 g (95.4 %) of light brown oil.
NMR data: (CDC13), 1H NMR (500 MHz): 8.02 ppm (H-26 and H-26', 2), m (d), J=8.4 Hz; 7.63-7.56 ppm (H-27, H-27', H-30 and H-30', 4), m, (in: 7.60 ppm (H-27 and H-27', 2), m (d), J=8.3 Hz and 7.59 ppm (H-30 and H-30', 2), m (d), J-7.1 Hz); 7.45 ppm (H-31 and Η-3Γ, 2), m (t), J-7.4 Hz; 7.38 ppm (H-32, 1), m (t/tt), J=7.3 Hz; 7.15 ppm (H-22, 1), m (t), J=7.8 Hz; 6.83- 6.76 ppm (H-21 and H-23, 2), m (in: 6.79 ppm (H-21 and H-23, 2), m); 5.635 ppm (H-13, 1), dd, J=15.4 Hz and 7.6 Hz; 5.54 ppm (H-14, 1), m (dd), J=15.4 Hz and 6.4 Hz, 5.09 ppm (H-ll, 1), td, J=9.5 Hz and 6.1 Hz, 4.085 ppm (H-15, 1), m (q), J=6.4 Hz, 3.82 ppm (H-2, 3), m (s), 2.79- 2.70 ppm (H-4a and H-7a, 2), m (in: 2.74 ppm (H-4a and H-7a, 2), m (dd), J-13.8 Hz and -5.5 Hz); 2.665 ppm (H-4b, 1), m (dd), J=14.9 Hz and 5.2 Hz, 2.57-2.41 ppm (H-7b, H-9 and H-lOa, 3), m (in: 2.51 ppm (H-7, 1), m (dd), J=14.6 Hz and 4.6 Hz; 2.48 ppm (H-9, 1), m; 2.47 ppm (H- 10a, 1), m); 2.25-2.11 ppm (H-8 and H-12, 2), m, (in: 2.20 ppm (H-12, 1), m and 2.18 ppm (H-8, 1), m); 1.68 ppm (OH-15, 1), broad; 1.60-1.39 ppm (H-16, 2), m, (in: 1.51 ppm (H-16a, 1), m and 1.45 ppm (H-16b, 1), m); 1.38-1.18 ppm (H-lOb, H-17, H-18 and H-19, 7), m, (in: 1.31 ppm (H-lOb and H-17a, 2), m; 1.25 ppm (H-17b, H-18 and H-19, 5) m); 0.85 ppm (H-20, 3), m (t), J=6.8 Hz 13C NMR (125.8 MHz): 166.50 ppm (C-24), 156.90 ppm (C-3), 145.71 ppm (C-28), 140.18 ppm (C-29), 139.89 ppm (C-6), 135.69 ppm (C-13), 131.52 ppm (C-14), 130.18 ppm (C- 26 and C-26', 2), 129.26 ppm (C-25), 129.03 ppm (C-31 and C-31 ', 2), 128.22 ppm (C-32), 127.38 ppm (C-30 and C-30', 2), 127.10 ppm (C-27 and C-27', 2), 126.55 ppm (C-5), 126.49 (C- 22), 120.87 ppm (C-23), 108.58 ppm (C-21), 77.84 ppm (C-11), 72.76 ppm (C-15), 55.68 ppm (C-2), 53.53 ppm (C-12), 40.14 ppm (C-8), 37.66 ppm (C-10), 37.26 ppm (C-16), 33.00 ppm (C- 9), 32.02 ppm (C-7), 31.86 ppm (C-18), 25.53 ppm (C-4), 25.12 ppm (C-17), 22.71 ppm (C-19), 14.14 ppm (C-20).
lm.) Preparation of (lR,3aS,9aS)-l-[(E)-3-hydroxyoct-l-enyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-lH- cyclopenta[b]naphthalen-2-ol (TREP-13)
TREP-12 TREP-13
M=524.71 M=344.50
17 g (32.4 mmol) of TREP-12 is dissolved in 70 ml of methanol, 4.2 g (30.3 mmol) of K2C03 is added and the mixture is stirred at 40°C till the end of the reaction. When the desired conversion is reached, the reaction mixture is cooled to 0°C and in portions phosporic acid solution is added to it. The precipitated p-phenylbenzoyl methyl ester (PPB-methyl ester) is filtered off and washed. The filtrate is concentrated, water and toluene are added to it and the phases are separated. The aqueous phase is extracted with toluene, the organic phase is dried over Na2S04, the drying material is filtered off, the filtrate is evaporated and purified by chromatography on silica gel column (using hexane: tert-butyl methyl ether mixture eluent). The main fraction is crystallized from the mixture of hexane and tert-butyl methyl ether. The precipitated crystals are filtered off, washed and dried.
Yield: 8 g (72 %) of white crystals. Mp: 75-77 °C.
NMR data: (CDC13), 1H NMR (500 MHz): 7.10 ppm (H-22, 1), t, J=7.8 Hz; 6.78-6.70 ppm (H- 21 and H-23, 2), m (in: 6.75 ppm (H-21, 1), m (d), J=8.3 Hz and 6.73 ppm (H-23, 1), m (d), J=7.4 Hz); 5.52-5.42 ppm (H-13 and H-14, 2), m (in: 5.47 ppm (H-13 and H-14, 2), m); 4.04 ppm (H-15, 1), m, J=6.5 Hz and 3.2 Hz; 3.80 ppm (H-2, 3), s; 3.70 ppm (H-ll, 1), td, J=10.1 Hz and 6.1 Hz; 2.70-2.46 ppm (H-4a, H-7a, H-7b, OH- 11 and OH- 15, 5), m (in: 2.66 ppm (H-4a, 1), m (dd), J=14.9 Hz and 6.2 Hz; 2.63 ppm (H-7a, 1), m (dd), J-14.9 Hz and -6.1 Hz; 2.59 ppm (H-4b, 1), m (dd), J=14.7 Hz and 5.6 Hz; 2.57 ppm (OH-11 and OH-15, 2), m (broad)); 2.40-2.27 ppm (H-7b and H-9, 2), m (in: 2.37 ppm (H-7b, 1), m (dd), J=14.3 Hz and 5.4 Hz; 2.32 ppm (H- 9, 1), m); 2.23-2.13 ppm (H-lOa, 1), m, (in: 2.19 ppm (H-lOa, 1), m (ddd), J=12.1 Hz, 7.4 Hz and 6.4 Hz); 2.02 ppm (H-8, 1), m (tt), J=10.9 Hz and 5.5 Hz; 1.71 ppm (H-12, 1), m; 1.57 ppm (H-16a, 1), m; 1.48 ppm (H-16b, 1), m; 1.43-1.23 ppm (H-17, H-18 and H-19, 6), m, (in: 1.37 ppm (H-17a, 1), m; 1.33 ppm (H-19, 2), m; 1.325 ppm (H-17b, 1), m; 1.32 ppm (H-18, 2), m); 1.08 ppm (H-lOb, 1) m(dt/q), J=l 1.7 Hz and 10.5 Hz; 0.91 ppm (H-20, 3), m (t), J=6.9 Hz; 13C
NMR (125.8 MHz): 156.81 ppm (C-3), 140.33 ppm (C-6), 136.20 ppm (C-14), 133.38 ppm (C- 13), 126.87 ppm (C-5), 126.38 (C-22), 120.77 ppm (C-23), 108.58 ppm (C-21), 75.87 ppm (C- 11), 73.32 ppm (C-15), 56.94 ppm (C-12), 55.71 ppm (C-2), 40.61 ppm (C-8), 40.49 ppm (C- 10), 37.29 ppm (C-16), 32.73 ppm (C-9), 32.21 ppm (C-7), 31.85 ppm (C-18), 25.54 ppm (C-4), 25.37 ppm (C-17), 22.78 ppm (C-19), 14.18 ppm (C-20).
In.) Preparation of (lR,3aS,9aS)-l-(3-hydroxyoctyl)-5-methoxy-2,3,3a,4,9,9a-hexahydro-lH- cyclopenta[b]naphthalen-2-ol (TREP- 14)
TREP-13 TREP-14
=344.49 M=346.51
C22H32O3 C22H34O3
In the mixture of 77 ml of methyl ethyl ketone and 154 ml of ethanol 7.7 g (22.3 mmol) of TREP-13 is dissolved. The reaction mixture is hydrogenated under 6 bar pressure over 0.77 g of 10% palladium on charcoal catalyst desactivated with sodium nitrite. At the end of the reaction the catalyst is filtered off, washed with ethyl acetate, the filtrate is evaporated in vacuum and the residue is crystallized from hexane: ethyl acetate mixture.
Yield: 6.4 g (83 %) of white crystals. Mp: 71-72 °C.
NMR data: (CDC13), 1H NMR (500 MHz): 7.09 ppm (H-22, 1), t, J=7.8 Hz; 6.78-6.71 ppm (H- 21 and H-23, 2), m (in: 6.75 ppm (H-23, 1), m (d), J-7.4 Hz and 6.74 ppm (H-21, 1), m (d), J=8.1 Hz); 3.80 ppm (H-2, 3), s; 3.71 ppm (H-11, 1), td, J=9.6 Hz and 6.1 Hz; 3.59 ppm (H-15, 1), m; 2.83-2.69 ppm (H-4a and H-7a, 2), m (in: 2.79 ppm (H-4a, 1), m (dd), J=14.7 Hz and 6.1 Hz; 2.74 ppm (H-7a, 1), m (dd), J=14.3 Hz and 6.2 Hz); 2.51-2.40 ppm (H-4b es H-7b, 2), m (in: 2.47 ppm (H-4b, 1), m (dd), J=14.8 Hz and 6.5 Hz; 2.44 ppm (H-7b, 1), m (dd)), J=14.4 Hz and
6.6 Hz); 2.40-2.19 ppm (H-9 and OH-ll/OH-15, 2), m (in: 2.31 ppm (OH-ll/OH-15, 1), broad and 2.22 ppm (H-9, 1), m, J=10.2 Hz and -7.0 Hz); 2.19-1.97 ppm (H-lOa and OH-ll/OH-15, 2), m, (in: 2.155 ppm (H-lOa, 1), m (ddd), J=11.7 Hz, 7.4 Hz and 6.1 Hz and 2.08 ppm (OH- ll/OH-15, 1), broad); 1.92-1.74 ppm (H-8 and H-ll/H-15/water, 2), m, (in: 1.87 ppm (H-8, 1), m (tt), J=10.0 Hz and 6.4 Hz and 1.81 ppm (OH-ll/OH-15, 1), broad); 1.69-1.50 ppm (H-13 and H- 14, 4), m (in: 1.62 ppm (H-13a and H-14a, 2) m; 1.57 ppm (H-13b, 1), m and 1.55 ppm (H-14b, 1), m); 1.50-1.38 ppm (H-16 and H-17a, 3), m (in: 1.47 ppm (H-16a, 1), m and 1.435 ppm (H- 16b, 1), m and 1.43 ppm (H-17a, 1), m); 1.38-1.22 ppm (H-12, H-17b, H-18 and H-19, 6), m (in: 1.32 ppm (H-19, 2), m; 1.31 ppm (H-17b, 1), m; 1.30 ppm (H-12 and H-18, 3), m); 1.14 ppm (H- 10b, 1), m (dt), J=11.5 Hz and 10.1 Hz; 0.90 ppm (H-20, 3), m (t), J=6.9 Hz; 13C NMR (125.8 MHz): 156.64 ppm (C-3), 140.65 ppm (C-6), 127.09 ppm (C-5), 126.26 (C-22), 120.60 ppm (C- 23), 108.51 ppm (C-21), 77.51 ppm (C-ll), 72.70 ppm (C-15), 55.72 ppm (C-2), 52.40 ppm (C- 12), 41.54 ppm (C-10), 41.44 ppm (C-8), 37.58 ppm (C-16), 35.14 ppm (C-14), 33.82 ppm (C- 7), 32.96 ppm (C-9), 32.05 ppm (C-18), 28.77 ppm (C-13), 25.88 ppm (C-4), 25.52 ppm (C-17), 22.78 ppm (C-19), 14.18 ppm (C-20).
lo.) Preparation of (lR,2R,3aS,9aS)- l-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-lH- benz[f]indene-2,5-diol (TREP-15)
TREP-14 TREP-15
To 2.4 1 of 1-dodecanethiol under nitrogen atmosphere 400 g of water-free aluminum chloride is added. The mixture is cooled to 0-5°C and the solution of 200 g of TREP-14 in 560 ml of dichloromethane is added to it. The reaction mixture is stirred at room temperature. At the end of the reaction the mixture is poured onto 4 1 of water and then 664 ml of 2M sodium hydrogen sulfate is added. The phases are separated, the aqueous phase is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is crystallized from hexane. The crystals are filtered off, washed and recrystallized from hexane: ethyl acetate mixture.
Yield: 182 g (95%) of white crystals. Mp: 113-115 °C.
NMR data: (CDC13), 1H NMR (500 MHz): 6.99 ppm (H-22, 1), t, J=7.7 Hz; 6.73 ppm (H-23, 1), d, J=7.4 Hz; 6.65 ppm (H-21, 1), d, J=8.0 Hz; 4.95 ppm (OH-3, 1), s; 3.75 ppm (H-11, 1), td, J=9.4 Hz and 6.2 Hz; 3.62 ppm (H-15, 1), m; 2.78-2.675 ppm (H-4a and H-7a, 2), m (in: 2.735 ppm (H-7a, 1), m (dd), J=14.0 Hz and 7.0 Hz; 2.72 ppm (H-4a, 1), m (dd), J=14.6 Hz and 6.5 Hz); 2.51-2.42 ppm (H-4b and H-7b, 2), m (in: 2.47 ppm (H-4b, 1), m (dd), J=14.6 Hz and 6.3 Hz; 2.46 ppm (H-7b, 1), m (dd)), J=14.2 Hz and 6.2 Hz); 2.28 ppm (H-9, 1), m, J=10.3 Hz, -7.3 Hz and -6.5 Hz; 2.175 ppm (H-lOa, 1), m (ddd/dt), J=12.0 Hz, 7.3 Hz and 6.4 Hz; 1.95-1.85 ppm (H-8, 1), m (in: 1.90 ppm (H-8, 1), m (tt), J=10.0 Hz and 6.2 Hz); 1.72-1.61 ppm (H-13a and H-14a, 2), m (in: 1.655 ppm (H-14a, 1), m and 1.65 ppm (H-14a, 1), m); 1.61-1.51 ppm (H- 13b and H-14b, 2), m (in: 1.56 ppm (H-14b, 1), m and 1.55 ppm (H-13b, 1), m); 1.51-1.385 ppm (H-16 and H-17a, 3), m (in: 1.48 ppm (H-16a, 1), m and 1.44 ppm (H-16b and H-17a, 2), m); 1.385-1.22 ppm (H-12, H-17b, H-18 and H-19, 6), m (in: 1.32 ppm (H-19, 2), m; 1.31 ppm (H- 17b, 1), m; 1.305 ppm (H-18, 2), m; 1.285 ppm (H-12, 1), m); 1.16 ppm (H-lOb, 1), dt, J=11.8 Hz and 10.2 Hz; 0.90 ppm (H-20, 3), m (t), J=6.9 Hz;
13C NMR (125.8 MHz): 152.65 ppm (C-3), 141.00 ppm (C-6), 126.39 (C-22), 124.60 ppm (C- 5), 120.67 ppm (C-23), 113.15 ppm (C-21), 77.56 ppm (C-ll), 72.79 ppm (C-15), 52.30 ppm (C- 12), 41.50 ppm (C-10), 41.41 ppm (C-8), 37.58 ppm (C-16), 35.09 ppm (C-14), 33.74 ppm (C- 7), 33.00 ppm (C-9), 32.05 ppm (C-18), 28.78 ppm (C-13), 26.12 ppm (C-4), 25.52 ppm (C-17), 22.79 ppm (C-19), 14.20 ppm (C-20).
lp.) Preparation of 2-[[(lR,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-l-[(3S)-3- hydroxyoctyl]-lH-benz[f]inden-5-yl]oxy]acetic acid ethyl ester (TREP-16 )
TREP-15 TREP-16
M: 332.48 M: 418.57
170 g (0.51 mol) of TREP-15 is dissolved in 3.4 1 of acetone. To the solution 340 g (2.46 mol) of anhydrous potassium carbonate and 89.6 g (0.536 mol) of bromoacetic acid ethyl ester are added and the mixture is stirred at 30-35 °C. At the end of the reaction the reaction mixture is filtered, the filtrate is evaporated. From the residue the product is crystallized with TBME (tert-butyl methyl ether): hexane mixture, filtered off, washed and dried.
Yield: 203 g (95%) of white crystals. Mp: 53-55 °C.
NMR data:
(CDC13, 1H NMR (500 MHz): 7.03 ppm (H-22, 1), t, J=7.8 Hz; 6.78 ppm (H-23, 1), d, J=7.4 Hz; 6.605 ppm (H-21, 1), d, J=8.2 Hz; 4.58 ppm (H-2, 2), s; 4.23 ppm (H-24, 2), q, J=7.1 Hz; 3.66 ppm (H-l l, 1), td, J=9.6 Hz and 6.2 Hz; 3.55 ppm (H-15, 1), m; 2.87 ppm (H-4a, 1), dd, J=14.7 Hz and 6.1 Hz; 2.80-2.455 ppm (H-4b, H-7a, OH-11 and OH-15, 4), m (in: 2.72 ppm (H- 7a, 1), dd, J=14.2 Hz and 6.2 Hz; 2.67 ppm (OH-11 and OH-15, 2), 2.50 ppm (H-4b, 1), dd, J=14.7 Hz and 6.7 Hz); 2.42 ppm (H-7b, 1), dd, J=14.2 Hz and 6.8 Hz; 2.25-2.07 ppm (H-9 and H-lOa, 2), m, (in: 2.20 ppm (H-9, 1), m, J=10.2 Hz, -6.5-7.1 Hz; 2.125 ppm (H-lOa, 1), m (ddd/dt), J-12.0 Hz, -7.2 Hz and -6.2 Hz), 1.83 ppm (H-8, 1), m (tt), J=9.9 Hz and 6.6 Hz; 1.70- 1.57 ppm (H-13a and H-14a, 2), m (in: 1.635 ppm (H-14a, 1), m and 1.625 ppm (H-14a, 1), m); 1.57-1.36 ppm (H-13b , H-14b, H-16 and H-17a, 5), m (in: 1.50 ppm (H-14b, 1), m; 1.48 ppm (H-13b, 1), m; 1.435 ppm (H-16a, 1), m; 1.415 ppm (H-17a, 1), m, 1.40 ppm (H-16b, 1), m); 1.36-1.19 ppm (H-12, H-17b, H-18, H-19 and H-25, 9), m (in: 1.295 ppm (H-19, 2), m; 1.28 ppm (H-17b, 1), m; 1.275 ppm (H-18, 2), m; 1.27 ppm (H-25, 3), t, J=7.1 Hz; 1.24 ppm (H-12, 1), m); 1.14 ppm (H-lOb, 1), dt, J=11.6 Hz and 10.2 Hz; 0.88 ppm (H-20, 3), t, J=6.9 Hz;
13C NMR (125.8 MHz): 169.32 ppm (C-l), 154.94 ppm (C-3), 141.15 ppm (C-6), 127.92 (C-5), 126.11 ppm (C-22), 121.55 ppm (C-23), 109.76 ppm (C-21), 77.16 ppm (C-ll), 72.47 ppm (C- 15), 66.12 ppm (C-2), 61.26 ppm (C-24), 52.31 ppm (C-12), 41.27 ppm (C-8), 41.25 ppm (C- 10), 37.49 ppm (C-16), 35.06 ppm (C-14), 33.88 ppm (C-7), 32.80 ppm (C-9), 31.99 ppm (C- 18), 28.63 ppm (C-13), 26.08 ppm (C-4), 25.47 ppm (C-17), 22.71 ppm (C-19), 14.22 (C-25), 14.13 ppm (C-20).
lq.) Preparation of 2-[[(lR,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy- hydroxyoctyl]-lH-benz[fJinden-5-yl]oxy]acetic acid (treprostinil)
TREP-16 Treprostinil
M: 418.57 M: 390.52
180 g (0.43 mol) of TREP-16 (ethyl ester) is dissolved in 650 ml of tetrahydrofuran. Under nitrogen atmosphere, at room temperature 2.7 1 of 0.5 M sodium hydroxide solution is added and the reaction mixture is stirred at room temperature. At the end of the reaction the mixture is washed with distilled tert-butyl methyl ether. To the aqueous alkaline phase tert-butyl methyl ether is added and the pH of the mixture is set to pH <3 with 1M sodium hydrogen sulfate solution. The aqueous acidic phase is then extracted with tert-butyl methyl ether, the united organic phase is washed with water and evaporated.
Yield: 165g (98%) of crystallizing oil.
NMR data (d6-DMSO), 1H NMR (400 MHz): 12.915 (COOH-1, 1), broad; 7.03 ppm (H-22, 1), t, J=7.8 Hz; 6.76 ppm (H-23, 1), d, J=7.4 Hz; 6.68 ppm (H-21, 1), d, J=8.2 Hz; 4.62 ppm (H-2, 2), s; 4.47 ppm (OH-11, 1), broad; 4.21 ppm (OH-15, 1), broad; 3.47 ppm (H-11, 1), m (q), J-8.0 Hz; 3.35 ppm (H-15, 1), m, 2.80-2.60 ppm (H-4a and H-7a, 2), m (in: 2.725 ppm (H-4a, 1), dd, J=14.7 Hz and 6.2 Hz; 2.67 ppm (H-7a, 1), dd, J=14.2 Hz and 6.2 Hz); 2.48-2.34 ppm (H-4b and H-7b, 2), m (in: 2.49 ppm (H-4b, 1), dd, J=14.6 Hz and 6.6 Hz; 2.39 ppm (H-7b, 1), dd, J=14.2 Hz and 6.5 Hz); 2.11 ppm (H-9, 1), m (tq), J-10.1 Hz and -6.7 Hz; 1.955 ppm (H-10a, 1), m (ddd/dt), J=12.1 Hz and 6.7 Hz; 1.76 ppm (H-8, 1), m (tt), J=10.0 Hz and 6.2 Hz; 1.61 ppm (H- 13a, 1) m; 1.53-1.33 ppm (H-14, H-16a and H-17a, 4), m (in:1.46 ppm (H-14a, 1), m; 1.43 ppm (H-14b, 1), m; 1.38 ppm (H- 17a, 1), m; 1.35 ppm (H- 16a, l), m); 1.33-1.15 ppm (H-13b, H-16b, H-17b, H-18 and H-19, 7), m (in: 1.32 ppm (H-13b, 1), m; 1.30 ppm (H-16b, 1), m; 1.275 ppm (H-19, 2), m; 1.26 ppm (H-17b, 1), m; 1.25 ppm (H-18, 2), m); 1.15-0.93 ppm (H-lOb and H-13, 2), m (in: H-1.09 ppm (H-12, 1), m (tt), J=9.0 Hz and 6.1 Hz; 1.00 ppm (H-lOb, 1), m (ddd/dt), J=11.7 Hz and 10.2 Hz); 0.87 ppm (H-20, 3), m (t), J=6.9 Hz;
13C NMR (100 MHz): 170.36 ppm (C-l), 154.63 ppm (C-3), 140.56 ppm (C-6), 126.75 ppm (C- 5), 125.85 (C-22), 120.65 ppm (C-23), 109.37 ppm (C-21), 75.44 ppm (C-11), 70.13 ppm (C-15), 64,96 ppm (C-2), 51.49 ppm (C-12), 41.15 ppm (C-10), 40.48 ppm (C-8), 37.06 ppm (C-16), 35.03 ppm (C-14), 33.37 ppm (C-7), 32.42 ppm (C-9), 31.53 ppm (C-l 8), 28.36 ppm (C-l 3), 25.62 ppm (C-4), 24.96 ppm (C-17), 22.18 ppm (C-19), 13.96 ppm (C-20).
Is.) Preparation of (lR,2R,3aS,9aS)-2-[2-Hydroxy-l-[3(S)-hydroxyoctyl]-2,3,3a,4,9,9a- hexahydro-lH-benz[fJinden-5-yloxy]acetic acid sodium salt (treprostinil sodium salt)
Qww
0 H 0 H
T Na salt
lsl.) 150 g (0.384 mol) of treprostinil is dissolved in 2 1 of ethanol. Sodium carbonate monohydrate 26.2 g (0.211 mol) is added to it and under an inert atmosphere the mixture is stirred at room temperature. When the pH of a filtered sample reaches the value of 7-9, the mixture is filtered through a 5 μπι pore size filter. The filtrate solution is concentrated on rotadest to approx. 225 g. The concentrate is dissolved in tert-butyl methyl ether which has been saturated with water and allowed to crystallize at room temperature. The crystals are filtered off, washed at room temperature and dried in vacuum at 20-50°C.
Yield: 158 g (100%) of treprostinil sodium salt monohydrate (form„A"), white crystals. Mp: 95- 99 °C.
Is2.) 150 g (0.384 mol) of treprostinil is dissolved in 2 1 of ethanol. 35.5 g (0.422 mol) of sodium hydrogen carbonate is added to it and under an inert atmosphere the mixture is stirred at room temperature. When the pH of a filtered sample reaches the value of 7-8, the mixture is filtered through a 5 μπι pore size filter and the filtrate solution is concentrated on rotadest to approx. 225 g. The concentrate is dissolved in tert-butyl methyl ether which has been saturated with water and allowed to crystallize at room temperature. The crystals are filtered off, washed at room temperature and dried in vacuum at 20-50°C.
Yield: 158 g (100%) of treprostinil sodium salt monohydrate (form„A"), white crystals. Mp: 95- 99 °C.
Is3.) 150 g (0.384 mol) of treprostinil is dissolved in 2 1 of ethanol. 21 g (0.39 mol) of sodium methylate is added to it and under an inert atmosphere the mixture is stirred at room temperature until dissolution. The solution is filtered through a 5 μπι pore size filter. The filtrate solution is
concentrated on rotadest to approx. 225 g. The concentrate is dissolved in tert-butyl methyl ether which has been saturated with water and allowed to crystallize at room temperature. The crystals are filtered off, washed at room temperature and dried in vacuum at 20-50°C.
Yield: 158 g (100%) of treprostinil sodium salt monohydrate (form„A"), white crystals. Mp: 95- 99 °C.
Is4.) 24 g (61.45 mmol) of treprostinil is dissolved in 360 ml of ethanol and 7.62 g (61.45 mmol) of sodium carbonate monohydrate is added to it. The mixture is stirred under an inert atmosphere at room temperature till complete dissolution. The solution is then filtered through a 5 μπι pore size filter and the filtrate solution is concentrated on rotadest. To the concentrate ethanol is added and the solution is concentrated again. The concentrate is dissolved in tert-butyl methyl ether and allowed to crystallize at room temperature. The crystals are collected by filtration, washed and dried in vacuum at 20-50°C.
Yield: 22.8 g (90%) of treprostinil sodium salt, white solid (amorphous form).
Mp: 65-90 °C
Analytical characterisation of treprostinil sodium salt monohydrate (form„A"):
Mp: 81-109 °C
DSC peak: 94-99 °C
Purity: 99.9 by HPLC area% 15-epi-treprostinil: 0.0 by HPLC area% Water content: 4.3 %
Specific optical rotation (c = 1 %, methanol 25 °C): + 41 ° Sulfated ash: 16.8 %
NMR data: (d6-DMSO), 1H NMR (500 MHz): 6.95 ppm (H-22, 1), t, J=7.8 Hz; 6.65 ppm (H-23, 1), d, J=7.4 Hz; 6.61 ppm (H-21, 1), d, J=8.2 Hz; 4.97-3.93 ppm (H-2, OH-11 and OH-15, 4), m (in: 4.54 ppm (OH-11, 1), broad; 4.32 ppm (OH-15, 1), broad; 4.13 ppm (H-2, 2), s); 3.47 ppm
(H-ll, 1), td, J=9.4 Hz and 6.2 Hz; 3.35 ppm (H-15, 1), m (tt), J-7.0 Hz and 4.3 Hz; 2.75 ppm (H-4a, 1), dd, J=14.5 Hz and 6.1 Hz; 2.65 ppm (H-7a, 1), dd, J=14.1 Hz and 6.1 Hz; 2.42-2.32 ppm (H-4b and H-7b, 2), m (in: 2.38 ppm (H-4b, 1), dd, J=14.5 Hz and 6.8 Hz; 2.355 ppm (H- 7b, 1), dd, J=14.1 Hz and 6.9 Hz); 2.08 ppm (H-9, 1), m (tq), J-10.1 Hz and -7.0 Hz; 1.96 ppm (H-lOa, 1), m (ddd/dt), J=12.1 Hz and 6.6 Hz; 1.73 ppm (H-8, 1), m (tt), J=9.8 Hz and 6.7 Hz; 1.61 ppm (H-13a, 1) m; 1.52-1.32 ppm (H-14, H-16a and H-17a, 4), m (in:1.455 ppm (H-14a, 1), m; 1.42 ppm (H- 14b, l), m; 1.38 ppm (H- 17a, l), m; 1.34 ppm (H- 16a, l), m); 1.32-1.16 ppm (H-13b, H-16b, H-17b, H-18 and H-19, 7), m (in: 1.31 ppm (H-13b, 1), m; 1.285 ppm (H-16b, 1), m; 1.275 ppm (H-19, 2), m; 1.26 ppm (H-17b, 1), m; 1.25 ppm (H-18, 2), m); 1.11 ppm (H- 12, 1), m (tt), J=9.0 Hz and 6.3 Hz, 1.02 ppm (H-lOb, 1), m (ddd/dt), J=11.3 Hz and 10.3 Hz); 0.865 ppm (H-20, 3), m (t), J=6.9 Hz;
13C NMR (125.8 MHz): 171.55 ppm (C-l), 155.89 ppm (C-3), 139.91 ppm (C-6), 126.38 ppm (C-5), 125.52 (C-22), 119.30 ppm (C-23), 109.74 ppm (C-21), 75.53 ppm (C-11), 70.14 ppm (C-
15) , 68,29 ppm (C-2), 51.58 ppm (C-12), 41.26 ppm (C-10), 40.63 ppm (C-8), 37.06 ppm (C-
16) , 35.07 ppm (C-14), 33.59 ppm (C-7), 32.55 ppm (C-9), 31.54 ppm (C-18), 28.40 ppm (C- 13), 25.82 ppm (C-4), 24.97 ppm (C-17), 22.19 ppm (C-19), 13.98 ppm (C-20).
DSC diagram of treprostinil sodium salt monohydrate (form„A") is shown on Figures 15 and 16. XRPD diagram of treprostinil sodium salt monohydrate (form„A") is shown on Figure 20.
It.) Preparation of treprostinil sodium salt anhydrate (form„B") Mp.: 125-129 °C):
111.) Any of the procedures of Examples Isl-ls2-ls3 may be followed with the exception that: the obtained crystals are filtered off, washed and dried in vacuum at 60-100°C.
It2.) Any of the procedures of examples Isl-ls2-ls3 may be followed, the obtained crystals are dried in vacuum at 60-100°C.
It3.) Treprostinil sodium salt monohydrate is agitated in suspension at 60-90 °C for 1-6 hours in a solvent which does not or only sparingly dissolves it. The solvent may be e.g. hexane, heptane, toluene or ethyl acetate.
DSC diagram of treprostinil sodium salt anhydrate (form„B") is shown on Figures 17 and 18.
XRPD diagram of treprostinil sodium salt anhydrate (form„B") is shown on Figure 21. lv.) Preparation of treprostinil sodium salt polyhydrate (form„C"):
1 vl .) Treprostinil sodium salt monohydrate (form„A") is kept in manipulator under an atmosphere of 60% moisture content for 48 hours, or treprostinil sodium salt monohydrate is kept under air for 5-8 days.
Iv2.) Treprostinil sodium salt anhydrate (form„B") is kept in manipulator under an atmosphere of 60% moisture content for 48 hours, or is kept under air for 5-8 days.
DSC diagram of treprostinil sodium salt polyhydrate (form„C") is shown on Figure 19.
XRPD diagram of treprostinil sodium salt polyhydrate (form„C") is shown on Figure 22.
DSC diagram of treprostinil sodium salt (amorphous form) is shown on Figure 14.
Characterisation of treprostinil sodium salts:
Termogravimetric analysis (TGA) has been carried out by TGA/SDTA85 le, Mettler Toledo instrument.
Differential scanning calorimetrical analysis has been carried out by DSC 1 Star6 System, Mettler Toledo.
XRPD analysis has been carried out by XPERT-PRO-PANalytical instrument.
Following experimental conditions have been used:
X-ray tube name: PW3373/10 Cu, anode material: Cu
Used wavelength: intended wavelength type: α, Κ ι (A): 1,540598
Scan range (°): 2,0000-40,0014
Example 2.)
2a.) Preparation of 2-pent-4-ynoxy-tetrahydropyran (MPKO-1)
CsHsO CsHsO CioHie02
M: 84.12 M: 84.12 : 168.24
In 5.5 1 of distilled toluene 552 g of 4-pentyn-l-ol is dissolved. To the solution are added 677 ml of dihydropyran and the solution of 19.5 g of para-toluenesulfonic acid (PTSA) in 120 ml tetrahydrofuran. The reaction mixture is stirred at room temperature. At the end of the reaction the mixture is quenched with triethylamine, washed with sodium hydrogen carbonate solution and with water. The organic phase is evaporated. The crude product is taken into the next step without purification.
Yield: 1062 g (96%) of colourless oil. NMR data:
(CDC13), 1H NMR (500 MHz): 4.59 ppm (H-6, 1), dd, J=4.0 Hz and 3.1 Hz; 3.90-3.79 ppm (H- la and H-lOa, 2), m, (in: 3.86 ppm (H-lOa, 1), ddd, J=11.3 Hz, 8.2 Hz and 3.2 Hz; 3.82 ppm (H- la, 1), dt, J=9.8 Hz and 6.2 Hz); 3.54-3.44 ppm (H-lb and lOHb, 2), m, (in: 3.50 ppm (H-lOb, 1), m; 3.48 ppm (H-lb, 1), dt, J=9.8 Hz and 6.2 Hz); 2.31 ppm (H-3, 2), m (tdd), J=7.1 Hz, 2.5 Hz and 1.5 Hz; 1.94 ppm (H-5, 1), t, J=2.6 Hz; 1.87-1.765 ppm (H-2 and H-8a, 3), m (tt/qui), (in: 1.81 ppm (H-2, 2), qui/tt, J=6.6 Hz; 1.82 ppm (H-8a, 1), m); 1.70 ppm (H-7a, 1), m; 1.615-1.47 ppm (H-7a, H-8a, H-9, 4), m, (in: 1.58 ppm (H-7b, 1), m; 1.57 ppm (H-9a, 1), m, 1.525 ppm (H- 9b, 1), m; 1.52 ppm (H-8b, 1), m);
13C NMR (125.8 MHz): 98.95 ppm (C-6), 84.13 ppm (C-4), 68.56 ppm (C-5), 65.93 ppm (C-1),
62.35 ppm (C-10), 30.81 ppm (C-7), 28.84 ppm (C-2), 25.61 ppm (C-9), 19.65 ppm (C-8), 15.48 ppm (C-3).
2b.) Preparation of l-(2-allyl-3-methoxyphenyl)-6-tetrahydropyran-2-yloxy-hex-2-yn-l-ol
(MPK-1)
MPKO-1 VPK-5 MPK-1
S10H16O2
M: 168.24 : 176.22 M: 344.45
In an inert atmosphere 1062 g of MPKO-1 is dissolved in 8.5 1 of anhydrous tetrahydrofuran and then at 60-65 °C 1920 ml of ethyl magnesium bromide solution (3M solution in ether) is slowly added. The reaction mixture is stirred for 45 minutes, cooled and then the solution of 927 g of VPK-5 (2-allyl-3-methoxybenzaldehyde) in 930 ml of tetrahydrofuran is added to it. At the end of the reaction the mixture is quenched with 1M NaHSC<4 solution, the aqueous phase is extracted with ethyl acetate, the united organic phase is washed with 0.5M NaHC03 solution and 15% NaCl solution, dried and concentrated to 2.4 kg. The concentrated crude product is taken into the next step without purification.
Yield: 100% (1812 g) of MPK-1, as light brown oil. NMR data:
(CDC13), 1H NMR (500 MHz): 7.34 ppm (H-6, 1), dd, J=7.8 Hz and 0.7 Hz; 7.24 ppm (H-5, 1), m (t), J= 8.0 Hz, partly overlapped with the peak of the residual CDC13 solvent; 6.86 ppm (H-4, 1), d (dbroad), J= 8.0 Hz; 5.985 ppm (H-14, 1), ddt, J= 17.1 Hz, 10.2 Hz and 5.9 Hz; 5.62 ppm (H-7, 1), broad; 4.98 ppm (H-15a, 1), dq (ddt), J=10.1 Hz, 1.8 Hz and 1.6 Hz; 4.93 ppm (H-15b, 1), dq (ddt), J=17.1 Hz, 1.8 Hz and 1.7 Hz; 4.57 ppm (H-17, 1), m, J=2.5 Hz; 3.88-3.77 ppm (H- 12a, H-16 es H-21a, 5), m, (in: 3.85 ppm (H-21a, 1), m; 3.82 ppm (H-16, 3), s; 3.81 ppm (H-12a, 1), dd, 15.9 Hz and 6.2 Hz); 3.625 ppm (H-13a, 1), ddt, J=15.7 Hz, 5.8 Hz and 1.6 Hz; 3.55 ppm (H-13b, 1), ddt, J=15.7 Hz, 5.9 Hz and 1.6 Hz; 3.505-3.43 ppm (H-12b and H-21b, 2), m, (in:
3.47 ppm (H-21b, 1), m; 3.46 ppm (H-12b, 1), m); 2.37 ppm (H-10, 2), td, J=7.1 Hz and 1.8 Hz; 2.30 ppm (OH-7, 1), broad; 1.87-1.75 ppm (H-11 and H-19a, 3), m, (in: 1.815 ppm (H-11, 2), tt (qui), J=6.7 Hz; 1.81 ppm (H-19a, 1), m); 1.69 ppm (H-18a, 1), m; 1.62-1.45 ppm (H-18b, H-19b and H-20, 4), m, (in: 1.565 ppm (H-18b, 1), m; 1.56 ppm (H-20a, 1), m; 1.51 ppm (H-20b, 1), m; 1.505 ppm (H-l 9b, l) m);
13C NMR (125.8 MHz): 157.74 ppm (C-3), 140.75 ppm (C-l), 137.20 ppm (C-14), 127.52 ppm (C-5), 125.94 pm (C-2), 119.32 ppm (C-6), 114.86 ppm (C-15), 110.74 ppm (C-4), 98.90 ppm (C-17); 86.66 ppm (C-9), 80.55 ppm (C-8), 66.03 ppm (C-12), 62.32 ppm (C-21), 62.23 ppm (C- 7), 55.91 ppm (C-16); 30.77 ppm (C-18), 29.56 ppm (C-13), 28.82 ppm (C-ll), 25.57 ppm (C- 20), 19.63 ppm (C-19), 15.93 ppm (C-10).
2c.) Preparation of l-(2-allyl-3-methoxyphenyl)-6-tetrahydropyran-2-yloxy-hex-2-yn-l-one (MPK-2)
MPK-1 MPK-2
C21H2804 C21H2604
: 344.45 : 342.44
To 12 1 of ethyl acetate in an inert atmosphere 4 kg of pyridinium chlorochromate (PCC) and then 1.7 kg of anhydrous sodium acetate are added. The suspension is stirred at room temperature for 15 minutes, then the 2.4 kg of MPK-1 solution obtained in the previous step is added. At the end of the reaction diisopropyl ether and silica gel are added to the mixture. After 15-20 minutes of stirring the mixture is filtered, the silica gel is washed with ethyl acetate and the filtrate solution is evaporated. The crude product is purified by chromatography on silica gel column using gradient mixtures of hexane: ethyl acetate as eluent. The fractions which contain the product are collected, concentrated, washed with water, dried over sodium sulfate, the drying material is filtered off and the filtrate solution is evaporated.
Yield: 1246 g (69%) of light brown oil.
NMR data:
(CDC13), 1H NMR (500 MHz): 7.73 ppm (H-6, 1), dd, J=7.8 Hz and 0.7 Hz; 7.29 ppm (H-5, 1), t, J= 8.0 Hz; 7.04 ppm (H-4, 1), d (dbroad), J= 8.0 Hz; 5.97 ppm (H-14, 1), ddt, J= 17.1 Hz, 10.1 Hz and 6.2 Hz; 4.985 ppm (H-15b, 1), dq (ddt), J=17.1 Hz and 1.7 Hz; 4.94 ppm (H-15a, 1), dq (ddt), J=10.1 Hz and 1.6 Hz; 4.60 ppm (H-l l , 1), m (dd), J=4.0 Hz and 2.9 Hz; 3.91-3.81 ppm (H-12a, H-16 and H-21a, 5), m, (in: 3.86 ppm (H-12a, 1), m, 3.855 ppm (H-21a, 1), m; 3.85 ppm (H-16, 3), s); 3.78 ppm (H-13, 2), dt, J=6.2 Hz and 1.5 Hz; 3.55-3.46 ppm (H-12b and H-21b, 2), m, (in: 3.51 ppm (H-12b, 1), m (dt), J=9.9 Hz and 6.0 Hz; 3.50 ppm (H-21b, 1), m); 2.585 ppm (H-10, 2), td, J=7.1 Hz and 1.4 Hz; 1.925 ppm (H-ll, 2), tt (qui), J=6.6 Hz; 1.82 ppm (H-19a, 1), m; 1.71 ppm (H-18a, 1), m; 1.64-1.46 ppm (H-18b, H-19b and H-20, 4), m, (in: 1.575 ppm (H-18b, 1), m; 1.57 ppm (H-20a, 1), m; 1.53 ppm (H-20b, 1), m; 1.52 ppm (H-19b, 1) m); 13C NMR (125.8 MHz): 180.21 ppm (C-7), 158.20 ppm (C-3), 137.53 ppm (C-l), 136.90 ppm (C-
14) , 130.04 pm (C-2), 126.85 ppm (C-5), 124.75 ppm (C-6), 115.01 ppm (C-4), 114.89 ppm (C-
15) , 99.05 ppm (C-17); 95.03 ppm (C-9), 81.97 ppm (C-8), 65.84 ppm (C-12), 62.46 ppm (C- 21), 56.20 ppm (C-16); 30.78 ppm (C-18), 29.89 ppm (C-13), 28.23 ppm (C-l l), 25.58 ppm (C- 20), 19.68 ppm (C-19), 16.38 ppm (C-10).
2d.) Preparation of (15)-l-(2-allyl-3-methoxyphenyl)-6-tetrahydropyran-2-yloxy-hex-2-yn-l-ol (MPK-3)
MPK-2 MPK-3
C2 H2604 C21H2804
: 342.44 M: 344.45
Under an inert atmosphere 1246 g of MPK-2 is dissolved in 6.3 1 of anhydrous tetrahydrofuran. The solution is cooled to 0-5°C and 5.73 1 of R-(+)-2-methyl-CBS-oxazaborolidine in 1M toluene solution is added. The mixture is then cooled to (-40)-(-35)°C and 925 ml of borane- dimethyl sulfide complex is added. At the end of the reaction the mixture is quenched with methanol and 5% NH4C1 solution, the aqueous phase is extracted with ethyl acetate, the organic phase is washed with water, dried, filtered and evaporated. The crude product is purified by chromatography on silica gel column using hexane: ethyl acetate mixtures eluents.
Yield: 1178 g (94%) of light brown oil.
NMR data:
(CDC13), 1H NMR (500 MHz): 7.35 ppm (H-6, 1), d, J=7.8 Hz, 7.24 ppm (H-5, 1), m (t), J= 8.0 Hz, 6.86 ppm (H-4, 1), d, J= 8.1 Hz; 5.99 ppm (H-14, 1), ddt, J= 17.1 Hz, 10.3 Hz and 5.7 Hz; 5.62 ppm (H-7, 1), t, J=1.8 Hz; 4.98 ppm (H-15a, 1), dq, J=10.1 Hz es 1.8 Hz; 4.94 ppm (H-15b, 1), dq, J=17.2 Hz and 1.7 Hz; 4.57 ppm (H-17, 1), m, J=2.4 Hz; 3.91-3.74 ppm (H-12a, H-16 and H-21a, 5), m, (in: 3.84 ppm (H-21a, 1), m; 3.82 ppm (H-16, 3), s; 3.82 ppm (H-12a, 1), m); 3.63 ppm (H-13a, 1), ddt, J=15.6 Hz, 5.8 Hz and 1.7 Hz; 3.55 ppm (H-13b, 1), ddt, J=15.6 Hz, 5.8 Hz and 1.7 Hz; 3.51-3.41 ppm (H-12b and H-21b, 2), m, (in: 3.475 ppm (H-21b, 1), m; 3.47 ppm (H-12b, 1), m (dt), J=9.7 Hz and 6.1 Hz); 2.44-2.20 ppm (OH-7 and H-10, 3), m, (in: 2.37 ppm (H-10, 2), td, J=7.1 Hz and 1.6 Hz; 2.30 ppm (OH-7, 1), broad); 1.90-1.75 ppm (H-ll and H-19a, 3), m, (in: 1.815 ppm (H-ll, 2), tt (qui), J=6.7 Hz; 1.81 ppm (H-19a, 1), m); 1.69 ppm (H-18a, 1), m; 1.62-1.44 ppm (H-18b, H-19b and H-20, 4), m, (in: 1.57 ppm (H-18b, 1), m; 1.56 ppm (H- 20a, 1), m; 1.515 ppm (H-20b, 1), m; 1.51 ppm (H-19b, 1) m);
13C NMR (125.8 MHz): 157.76 ppm (C-3), 140.77 ppm (C-l), 137.20 ppm (C-14), 127.51 ppm (C-5), 125.96 pm (C-2), 119.33 ppm (C-6), 114.85 ppm (C-15), 110.75 ppm (C-4), 98.91 ppm (C-17); 86.66 ppm (C-9), 80.57 ppm (C-8), 66.03 ppm (C-12), 62.32 ppm (C-21), 62.24 ppm (C- 7), 55.91 ppm (C-16); 30.77 ppm (C-18), 29.56 ppm (C-13), 28.83 ppm (C-ll), 25.58 ppm (C- 20), 19.63 ppm (C-19), 15.93 ppm (C-10).
2e.) Preparation of [( 1 S)- 1 -(2-allyl-3-methoxyphenyl)-6-tetrahydropyran-2-yloxy-hex-2-yn- 1 - oxy]tert-butyldimethylsilane (MPK-4)
MPK-3 MPK-4
C27H4204Si
: 458.72
The crude MPK-3 obtained in the previous step (theoretical amount 1253 g) is dissolved in 10 1 of toluene and to the solution 409 g of imidazole is added. The reaction mixture is cooled to 5-10 °C and 2.02 1 of tert-butyldimethylchlorosilane (TBDMS-C1) in 50 % toluene solution is added. The mixture is stirred at room temperature. At the end of the reaction water is added to the mixture and the insoluble impurities are filtered off. The filtrate residue is washed with toluene, the phases of the filtrate are separated, the organic phase is evaporated. The crude product is purified by chromatography on silica gel column using hexane: ethyl acetate mixtures as eluent.
Yield: 1515 g (91 %) of light brown oil. NMR data:
(CDC13), 1H NMR (500 MHz): 7.27 ppm (H-6, 1), m (d/dd), J=8.0 Hz and 1.0 Hz, 7.21 ppm (H- 5, 1), t, J= 8.0 Hz; 6.81 ppm (H-4, 1), d(dd), J= 8.1 Hz and 0.7 Hz; 5.95 ppm (H-14, 1), dddd, J= 16.9 Hz, 10.3 Hz, 6.4 Hz and 5.4 Hz; 5.575 ppm (H-7, 1), t, J=1.7 Hz; 5.00-4.90 ppm (H-15, 2), m, (in: 4.97 ppm (H-15a, 1), dq, J-10.2 Hz and 1.6 Hz; 4.94 ppm (H-15b, 1), dq, J-16.9 Hz and 1.8 Hz); 4.55 ppm (H-17, 1), m; 3.87-3.73 ppm (H-12 the two diastereomers, H-16 and H-21a, 5), m, (in: 3.83 ppm (H-21a, 1), m; 3.81 ppm (H-16, 3), s; 3.780 ppm and 3.778 ppm (H-12a, 1), dt, J=9.8 Hz and 6.3 Hz); 3.61 ppm (H-13a, 1), ddt, J=15.6 Hz, 5.2 Hz and 1.8 Hz; 3.55-3.38 ppm (H-12b, H-13b and H-21b, 3), m, (in: 3.505 ppm (H-13b, 1), m (dd), J=15.6 Hz and 6.4 Hz; 3.46 ppm (H-21b, 1), m; 3.42 ppm (H-12b, 1), dt, J=9.8 Hz and 6.3 Hz); 2.295 ppm (H-10, 2), m (td), J=7.2 Hz and 1.9 Hz; 1.86-1.73 ppm (H-ll and H-19a, 3), m, (in: 1.805 ppm (H-19a, 1), m; 1.77 ppm (H-ll, 2), tt (qui), J=6.7 Hz); 1.68 ppm (H-18a, 1), m; 1.64-1.45 ppm (H-18b, H-19b es H-20, 4), m, (in: 1.56 ppm (H-20a, 1), m; 1.55 ppm (H-18b, 1), m; 1.51 ppm (H-20b, 1), m; 1.50 ppm (H-19b, 1) m); 0.91 ppm (H-24, H-25 and H-26, 9), m (s), 0.12 ppm (H-22/H-23, 3), s, 0.09 ppm (H-23/H-22, 3), s.
13C NMR (125.8 MHz): 157.47 ppm (C-3), 142.27 ppm (C-l), 136.71 ppm (C-14), 127.20 ppm (C-5), 124.75 pm (C-2), 118.64 ppm (C-6), 114.61 ppm (C-15), 109.88 ppm (C-4), 98.95 ppm (C-17); 85.12 ppm (C-9), 81.51 ppm and 81.50 ppm (C-8), 66.15 ppm and 66.13 ppm (C-12), 62.45 ppm (C-21), 62.30 ppm (C-7), 55.81 ppm (C-16); 30.79 ppm (C-18), 29.58 ppm (C-13), 28.86 ppm and 28.84 (C-11), 25.99 ppm (C-25, C-26 and C-27, 3), 25.60 ppm (C-20), 19.67 ppm (C-19), 18.45 ppm (C-24), 15.93 ppm (C-10), -4.36 ppm (C-22/C-23), -4.69 ppm (C-23/C-22).
2f.) Preparation of (9R)-9-[tert-butyl(dimethyl)silyl]oxy-5-methoxy-l-(3-tetrahydropyran-2- yloxypropyl)-3,3a,4,9-tetrahydrocyclopenta[b]naphthalen-2-one
(MPK-5)
C27H«0«Si complex CMH„05Si : 458.72 M: 486.73
In 11.5 1 of dimethoxyethan, in an inert atmosphere, 1427 g of MPK-4 is dissolved and then 1070 g of dicobalt octacarbonyl is added. The reaction mixture is stirred at room temperature for 2.5 hours, then it is heated to 60-70 °C and stirred for 3 hours. At the end of the reaction air is bubbled through the mixture. Bubbling is continued overnight. The reaction mixture is then filtered, washed with ethyl acetate and evaporated. The crude product is purified by chromatography on silica gel column using hexane: diisopropyl ether mixtures as eluent.
Yield: 1363 g (90 %) of light brown oil.
NMR data:
(CDC13), 1H NMR (500 MHz): 7.22 ppm (H-22, 1), t, J= 7.9 Hz; 6.96-6.87 ppm (H-23, 1), m (in: 6.93 ppm (H-23, 0.5) d, J=7.7 Hz; 6.90 ppm (H-23, 0.5), d, J=7.7 Hz); 6.78 ppm (H-21, 1), d, J= 8.1 Hz; 5.55 ppm (H-7, 0.5), s; 5.21 ppm (H-7, 0.5), s; 4.50 ppm (H-24, 0.5), m (dd), J=4.1 Hz and 2.9 Hz; 4.26 ppm (H-24, 0.5) , m (dd), J=4.1 Hz and 2.9 Hz; 3.84-3.74 ppm (H-2, H-28, 3.5), m (in: 3.81 ppm (H-2, 3), s; 3.78 ppm (H-28, 0.5), m (ddd), J=11.3 Hz, 8.2 Hz and 3.2 Hz); 3.70 ppmn (H-28, 0.5), ddd, J=11.3 Hz, 8.0 Hz and 3.2 Hz; 3.66-3.55 ppm (H-15a, 1), m (in: 3.63 ppm (H-15a, 0.5), dt, J=9.9 Hz and 5.3 Hz; 3.58 ppm (H-15a, 0.5), ddd, J=9.9 Hz, 7.4 Hz and 5.6 Hz); 3.55-3.47 ppm (H-4a, 1), m (in: 3.52 ppm (H-4a, 0.5), dd, J=17.1 Hz and 7.4 Hz; 3.51 ppm (H-4a, 0.5), dd, J=17.0 and 7.4 Hz); 3.43-3.27 ppm (H-9, H-15b, H-28b, 2.5), m (in: 3.38 ppm (H-28b, 1), m; 3.35 ppm (H-9, 1), m; 3.315 ppm (H-15b, 0.5), m(dt), J=9.9 Hz and 5.9 Hz); 3.06 ppm (H-15b, 0.5), ddd, J-9.5 Hz, 8.6 Hz and 4.8 Hz; 2.745-2.65 ppm (H-lOa, 1), m (in: 2.702 ppm (H-lOa, 0.5), dd, J= 8.8 Hz and 6.4 Hz; 2.700 ppm (H-lOa, 0.5), dd, J=18.8 Hz
and 6.4 Hz); 2.46-2.30 ppm (H-13, 2), m (in: 2.42 ppm (H-13a, 0.5), m; 2.40 ppm (H-13a, 0.5), m; 2.385 ppm (H-13b, 0.5), m; 2.34 ppm (H-13b, 0.5), m); 2.25-2.18 ppm (H-lOb, 1), m (in: 2.212 ppm (H-lOb, 0.5), dd, J=18.8 Hz and 1.3 Hz; 2.210 ppm (H-lOb, 0.5), dd, J=18.8 Hz and 1.3 Hz); 2.175-2.07 ppm (H-4b, 1), m (in: 2.13 ppm (H-4b, 0.5), dd, J=17.1 Hz and 8.9 Hz; 2.115 ppm (H-4b, 0.5), dd, J=17.1 and 8.9 Hz); 1.875-1.72 ppm (H-14a and H-26, 2), m (in: 1.80 ppm (H-26, 1), m; 1.78 ppm (H-14a, 0.5), m; 1.75 ppm (H-14a, 0.5), m); 1.72-1.58 ppm (H-14b and H-25a, 2), m (in: 1.64 ppm (H-25a, 1), m; 1.63 ppm (H-14b, 1), m); 1.58-1.38 ppm (H-25b, H-26b and H-27, 4), m (in: 1.53 ppm (H-25b, 1), m; 1.51 ppm (H-27b, 1) m; 1.48 ppm (H-26b,
1) , m; 1.41 ppm (H-27b, 1), m); 0.82 ppm (H-32, H-33 and H-34, 9), s; 0.16-0.12 ppm (H-29/H- 30, 3), m (s) (in: 0.143 ppm (H-29/H-30, 1.5), s; 0.135 ppm (H-29/H-30, 1.5), s); 0.10-0.055 ppm (H-30/H-29, 3), m (in: 0.082 ppm (H-30/H-29, 1.5), s, 0.077 ppm (H-30/H-29, 1.5), s, 13C NMR (125.8 MHz): 209.78 ppm (C-ll), 173.52 ppm and 173.25 ppm (C-8), 156.95 ppm and 156.92 ppm (C-3), 138.43 ppm and 138.36 ppm (C-6), 136.94 ppm and 136.64 ppm (C-12), 127.45 ppm and 127.39 ppm (C-22), 125.11 pm and 125.10 ppm (C-5), 122.25 ppm and 122.12 ppm (C-23), 109.32 ppm and 109.31 ppm (C-21), 98.82 ppm and 98.73 ppm (C-24), 66.64 ppm and 65.97 ppm (C-15), 65.34 ppm and 65.23 ppm (C-7), 62.36 ppm and 62.26 ppm (C-28), 55.45 ppm (C-
2) ; 42.32 ppm and 42.29 ppm (C-10) , 33.76 ppm and 33.50 ppm (C-4), 32.33 ppm and 32.31 ppm (C-9), 30.87 ppm and 30.84 ppm (C-25), 28.56 ppm and 28.21 ppm (C-14), 25.77 ppm (C- 32, C-33 and C-34, 3), 25.58 ppm (C-27), 19.80 ppm and 19.68 ppm (C-26), 18.21 ppm and 18.20 ppm (C-31), -4.01 ppm and -4.03 ppm (C-29/C-30), -4.15 ppm (C-30/C-29).
2g.) Preparation of (9aS)-5-methoxy-l-(3-tetrahydropyran-2-yloxypropyl)-l,3,3a,4,9,9a- hexahydrocyclopenta[b]naphth-2-one (MPK-6)
MPK-5 MPK-6
C28H4205Si
M: 486.73
1363 g MPK-5 is dissolved in 5.5 1 of ethyl alcohol, 60 g of potassium carbonate and 480 g of 10% Pd(C) catalyst are added and after proper inertisation the reaction mixture is stirred under 6 bar hydrogen pressure at room temperature. At the end of the reaction the catalyst is filtered off, washed with ethyl alcohol and the filtrate solution is evaporated. The crude product is purified by chromatography on silica gel column using hexane: ethyl acetate mixtures as eluent.
Yield: 703 g (70 %) of light brown oil.
NMR data:
(CDC13), 1H NMR (500 MHz): 7.10 ppm (H-22, 1), t, J=7.9 Hz, 6.74-6.64 ppm (H-21 and H-23, 2), m (in: 6.69 ppm (H-21, 1) d, J-8.4 Hz; 6.71 ppm (H-23, 1), d, J-8.3 Hz), 4.60 ppm (H-24, 1), m (dd), J=4.1 Hz and 3.0 Hz; 3.93-3.76 ppm (H-2, H-15a and H-28a, 5), m (in: 3.87 ppm (H-28a, 1), m; 3.82 ppm (H-2, 3), s; 3.805 ppm (H-15a, 1), m), 3.575-3.335 ppm (H-15b and H-28b, 2), m (in: 3.51 ppm (H-28b, 1), m; 3.44 ppm (H-15b, 1), m), 2.95 ppm (H-4a, 1), m (dd), J=18.3 Hz and 7.4 Hz, 2.80 ppm (H-4b, 1), d, J=18.2 Hz; 2.77-2.625 ppm (H-7a and H-9, 2), m (in: 2.74 ppm (H-7a, 0.5), m (dd), J=16.7 Hz and 5.9 Hz; 2.73 ppm (H-7a, 0.5), m (dd), J=16.7 Hz and 5.9 Hz; 2.68 ppm (H-9, 1), m), 2.56 ppm (H-8, 1), m (tt/qui), J=5.9 Hz and 5.5 Hz, 2.50-2.37 ppm (H-lOa and H-12, 2), m (in: 2.44 ppm (H-lOa, 1), dd, J=18.8 Hz and 8.2 Hz; 2.41 ppm (H-12, 1), m (ddd), J=5.5 Hz), 2.23 ppm (H-7b, 1), dd, J=16.5 Hz and 11.7 Hz, 2.00-1.79 ppm (H-lOb, H- 13a and H-26a, 3), m (in: 1.93 ppm (H-lOb, 1), dd, J=18.9 Hz and 12.1 Hz; 1.905 ppm (H-13a, 1), m; 1.84 ppm (H-26a, 1), m), 1.79-1.64 ppm (H-14 and H-25a, 3), m (in: 1.79 ppm (H-25a, 1), m; 1.76 ppm (H-14a, 1), m; 1.71 ppm (H-14b, 1), m), 1.64-1.39 ppm (H-13b, H-25b, H-26b and H-27, 5), m (in: 1.59 ppm (H-25b, 1), m; 1.57 ppm (H-27a, 1), m; 1.53 ppm (H-26b, 1), m; 1.52 ppm (H-27b, 1), m; 1.45 ppm (H-13b, 1), m), 13C NMR (125.8 MHz): 219.34 ppm (C-ll), 157.72 ppm (C-3), 136.06 and 136.04 ppm (C-6) 126.29 ppm (C-22), 123.37 ppm (C-5), 121.19 ppm (C-23), 107.46 ppm (C-21), 99.09 ppm and 98.96 ppm (C-24), 67.57 ppm and 67.45 ppm (C-15), 62.48 ppm (C-28), 56.82 ppm (C-12), 55.34 ppm (C-2), 41.86 ppm (C-10), 35.51 ppm (C-8), 31.69 ppm (C-9), 30.90 ppm and 30.87 ppm (C-25), 28.32 ppm and 28.28 ppm (C-14), 26.65 ppm (C-7), 25.60 ppm (C-27), 24.55 ppm (C-4), 21.48 ppm and 21.43 ppm (C-13), 19.77 ppm (C-26).
2h.) Preparation o(lR,2R,9aS)-5-methoxy-l-(3-tetrahydropyran-2-yloxypropyl)-2,3,3a,4,9,9a- hexahydro- 1 H-cyclopenta[b]naphth-2-ol (MPK-7)
703 g of MPK-6 is dissolved in 14 1 of ethyl alcohol, the solution is cooled and at (-)15-(-)10°C 42 g of sodium borohydride is added. The reaction mixture is agitated. At the end of the reaction the mixture is quenched with acetic acid and the ethyl alcohol is distilled off. After the addition of water and ethyl acetate the phases are separated, the aqueous phase is extracted with ethyl acetate. The united organic phase is washed with 1M NaHC03 solution and water, dried, filtered and evaporated. The crude product is taken into the next step without purification.
Yield: 636 g (90 %) of light brown oil.
NMR data:
(CDC13), 1H NMR (500 MHz): 7.125-7.04 ppm (H-22, 1), m (in: 7.09 ppm (H-22, 0.5), t, J=7.8 Hz; 7.08 ppm (H-22, 0.5), t, J=7.8 Hz); 6.79-6.71 ppm (H-21 and H-23, 2), m (in: 6.760 ppm (H- 21, 0.5), m (d), J=7.6 Hz; 6.754 ppm (H-21, 0.5), m (d), J=7.6 Hz; 6.738 ppm (H-23, 0.5), m (d), J-8.3 Hz; 6.735 ppm (H-23, 0.5), m (d), J=7.8 Hz); 4.63-4.52 ppm (H-24, 1), m (in: 4.585 ppm (H-24, 0.5), m (dd), J=4.1 Hz and 3.1 Hz; 4.56 ppm (H-24, 0.5), m (dd), J=4.3 Hz and 2.9 Hz); 3.87 ppm (H-28a, 0.5), m (ddd); 3.84-3.67 ppm (H-2, H-11, H-15a and H-28a, 5.5), m (in: 3.805 ppm (H-28a, 0.5), m; 3.80 ppm (H-2, 3), s; 3.795 ppm (H-15a, 0.5), m; 3.75 ppm (H-15a, 0.5), m; 3.715 ppm (H-11, 1), td, J=9.8 Hz and 6.2 Hz); 3.54-3.46 ppm (H-28b, 1), m (in: 3.50 ppm (H-28b, 0.5), m; 3.48 ppm (H-28b, 0.5), m); 3.46-3.36 ppm (H-15b, 1), m (in: 3.43 ppm (H-15b, 0.5), dt, J=9.6 Hz and 6.2 Hz; 3.40 ppm (H-15b, 0.5), dt, J=9.6 Hz and 6.5 Hz); 2.82-2.70 ppm (H-4a and H-7a, 2), m (in: 2.775 ppm (H-4a, 1), dd, J=14.6 Hz and 6.1 Hz; 2.746 ppm (H-7a, 0.5), m (dd), J=14.1 Hz and 6.2; 2.741 ppm (H-7a, 0.5), m (dd), J=14.3 Hz and 6.2); 2.54-2.41 ppm (H-4b and H-7b, 2), m (in: 2.497 ppm (H-4b, 0.5), m (dd), J=14.7 Hz and 6.5 Hz; 2.492
ppm (H-4b, 0.5), m (dd), J=14.7 Hz and 6.4 Hz; 2.455 ppm (H-7b, 1), dd, J=14.3 Hz and 6.4 Hz); 2.30-2.04 ppm (H-9, H-10 and OH-11, 2.5), m (in: 2.249 ppm (H-9, 0.5), m (tt), J=10.3 Hz and 6.9 Hz; 2.214 ppm (H-9, 0.5), m (tt), J=10.0 Hz and 6.8 Hz; 2.16 ppm (H-lOa, 1), m (dt/ddd), J=12.0 Hz, 7.1 Hz and 6.3 Hz; 2.15 ppm (OH-11, 0.5), broad); 2.00 ppm (OH-11, 0.5), 1.93-1.64 ppm (H-8, H-14, H-25a and H-26a, 5), m (in: 1.88 ppm (H-8, 1), m (tt), J=10.0 Hz and 6.3 Hz; 1.82 ppm (H-26a, 0.5), m; 1.795 ppm (H-14a, 1), m; 1.79 ppm (H-26a, 0.5), m; 1.755 ppm (H-14b, 1), m; 1.695 ppm (H-25a, 1), m); 1.64-1.44 ppm (H-13, H25b, H-26b and H-27, 6), m (in: 1.58 ppm (H-13a, 1), m; 1.565 ppm (H-25b, 1), m; 1.56 ppm (H-13b, 1), m; 1.555 ppm (H-27a, 1), m; 1.53 ppm (H-26b, 0.5), m; 1.505 ppm (H-27b, 1), m; 1.50 ppm (H-26b, 0.5), m); 1.38-1.20 ppm (H-12, 1), m (in: 1.32 ppm (H-12, 0.5), m, J-9.2 Hz and 6.6 Hz; 1.29 ppm (H-12, 0.5), m; J-9.2 Hz and 6.6 Hz), 1.19-1.08 ppm (H-10, 1), m (in: 1.16 ppm (H-lOb, 0.5), m (ddd), J-10.0 Hz; 1.12 ppm (H-lOb, 0.5), m (ddd), J-10.0 Hz);
13C NMR (125.8 MHz): 156.23 ppm (C-3), 140.64 ppm and 140.55 ppm (C-6), 127.04 ppm and 127.02 ppm(C-5) 126.20 ppm (C-22), 120.58 ppm (C-23), 108.43 ppm and 108.41 ppm (C-21), 99.09 ppm and 99.07 ppm (C-24), 77.37 ppm (C-ll), 68.39 ppm and 68.36 ppm (C-15), 62.52 ppm and 62.42 ppm (C-28), 55.67 ppm (C-2), 51.96 ppm (C-12), 41.61 ppm and 41.41 ppm (C- 8), 41.56 ppm and 41.53 ppm (C-10), 33.81 ppm and 33.76 ppm (C-7), 32.94 ppm (C-9), 30.81 ppm and 30.76 ppm (C-25), 29.90 ppm and 29.74 ppm (C-13), 27.73 ppm and 27.66 ppm (C-14), 25.83 ppm (C-4), 25.55 ppm and 25.52 ppm (C-27), 19.79 ppm and 19.69 ppm (C-26).
2i.) Preparation of [(lR,9aS)-5-methoxy-l-(3-tetrahydropyran-2-yloxypropyl)-2,3,3a,4,9,9a- hexahydro-lH-cyclopenta[b]naphth-2-yl] 4-phenylbenzoate (MPK-8)
MPK-7
MPK-8
M: 360.50
In an inert atmosphere 636 g of MPK-7 is dissolved in 1.4 1 of pyridine and 508 g of p-phenylbenzoyl chloride is added to the solution. The reaction mixture is stirred at
50-60 °C. At the end of the reaction water and tert-butyl methyl ether are added, the phases are separated, the aqueous phase is extracted with tert-butyl methyl ether. The united organic phase is washed consecutively with NaHS0 solution, K2CO3 solution and water, dried, filtered and evaporated. The crude product is purified by chromatography on silica gel using hexane: ethyl acetate mixtures as eluent.
Yield: 763 g (80 %) of white crystals. Mp: 140-143 °C. NMR data:
(CDC13), 1H NMR (500 MHz): 8.06 ppm (H-31 and Η-3Γ, 2), d, J=8.4 Hz; 7.66-7.58 ppm (H- 32, H-32', H-35 and H-35', 4), m (in: 7.63 ppm (H-32 and H-32', 2), m (d), J=8.5 Hz; 7.61 ppm (H-35 and H-35', 2), m (d), J=7.3 Hz); 7.46 ppm (H-36 and H-36', 2), m (t), J=7.5 Hz; 7.39 ppm (H-37, 1), m (t), J=7.4 Hz; 7.14 ppm (H-22, 1), t, J=7.8 Hz; 6.82 ppm (H-23, 1), m (d/dbroad), J=7.4 Hz; 6.77 ppm (H-21, 1), d, J=8.2 Hz; 5.03 ppm (H-ll, 1), td, J=8.4 Hz and 6.3 Hz; 4.565 ppm (H-24, 1), m; 3.895-3.79 ppm (H-2 and H-28a, 4), m (in: 3.85 ppm (H-28a, 1), m; 3.82 ppm (H-2, 3), s); 3.79-3.72 ppm (H-15a, 1), m (in: 3.758 ppm (H-15a, 0.5), dt, J=9.7 Hz and 6.6 Hz; 3.752 ppm (H-15a, 0.5), dt, J=9.7 Hz and 6.5 Hz); 3.48 ppm (H-28b, 1), m; 3.45-3.375 ppm (H- 15b, 1), m (in: 3.416 ppm (H-15b, 0.5), dt, J=9.6 Hz and 6.6 Hz; 3.410 ppm (H-15b, 0.5), dt, J=9.6 Hz and 6.4 Hz); 2.95-2.81 ppm (H-4a and H-7a, 2), m (in: 2.91 ppm (H-4a, 1), dd, J=14.9 Hz and 6.2 Hz; 2.85 ppm (H-7a, 1), dd, J=14.5 Hz and 6.3); 2.635-2.34 ppm (H-4b, H-7b, H-9 and H-10a, 4), m (in: 2.589 ppm (H-7b, 0.5), m (dd), J=14.4 Hz and 6.9 Hz; 2.587 ppm (H-7b, 0.5), m (dd), J=14.6 Hz and 7.0 Hz; 2.535 ppm (H-4b, 1), dd, J=14.9 Hz and 7.2 Hz; 2.48 ppm (H-lOa, 1), m (ddd), J=6.4 Hz; 2.40 ppm (H-9, 1), m, J-7.7 Hz); 2.03 ppm (H-8, 1), m (tt), J=9.1 Hz and 6.8 Hz; 1.88-1.45 ppm (H-12, H-13, H-14, H-25, H-26 and H-27, 11), m (in: 1.83 ppm (H-12, 1), m; 1.81 ppm (H-26a, 1), m; 1.77 ppm (H-14a, 1), m; 1.74 ppm (H-14b, 1), m; 1.69 ppm (H-25a, 1), m; 1.63 ppm (H-13a, 1), m; 1.60 ppm (H-13b, 1), m; 1.57 ppm (H-25b, 1), m; 1.55 ppm (H-27a, 1), m; 1.51 ppm (H-27b, 1), m; 1.50 ppm (H-26b, 1), m); 1.385 ppm (H-lOb, 1), dt, J=12.3 Hz and 8.7 Hz; 13C NMR (125.8 MHz): 166.44 ppm (C-29), 156.64 ppm (C-3), 145.64 ppm (C-33), 140.26 ppm (C-6); 140.21 ppm (C-34) ,130.20 ppm (C-31 es C-31', 2), 129.44 ppm (C-30), 129.03 ppm (C-36 and C-36', 2), 128.21 ppm (C-37), 127.39 ppm (C-35 and C-35', 2), 127.12 ppm (C-32 and C-32', 2), 126.83 ppm (C-5), 126.33 ppm (C-22), 120.58 ppm and 120.57 ppm (C-23) ,108.42 ppm (C-21), 99.02 ppm (C-24), 80.04 ppm and 80.00 ppm
(C-ll), 67.88 ppm and 67.84 ppm (C-15), 62.51 ppm and 62.49 ppm (C-28), 55.65 ppm (C-2), 49.58 ppm (C-12), 41.00 ppm and 40.99 ppm (C-8), 38.00 ppm (C-10), 33.85 ppm (C-9), 33.80 ppm (C-7), 30.89 ppm and 30.88 ppm (C-25), 29.61 ppm and 29.58 ppm (C-13), 27.91 ppm and 27.89 ppm (C-14), 25.92 ppm (C-4), 25.61 ppm (C-27), 19.81 ppm and 19.80 ppm (C-26).
2j .) Preparation of [( 1 R,2R,9aS)- 1 -(3 -hydroxypropyl)-5-methoxy-2,3 ,3 a,4,9,9a-hexahydro- 1 H- cyclopenta[b]naphth-2-yl] 4-phenylbenzoate (MPK-9)
MPK-8 MPK-9
M: 540.71 M: 456.59
574 g of MPK-8 is dissolved in 1.2 1 of tetrahydrofuran. 4.6 L of methanol, and then carefully the mixture of 145 ml of cone, hydrochloric acid and 145 ml of water are added. At the end of the reaction the mixture is quenched with 1M NaHC03 solution and the solvents are distilled off. The residual aqueous phase is extracted with ethyl acetate, the united organic phase is washed with water, dried, filtered and evaporated. The evaporated crude product is purified by chromatography on silica gel.
Yield: 376 g (78 %) of colourless oil.
NMR data:
(CDC13), 1H NMR (500 MHz): 8.05 ppm (H-31 and H-31 ', 2), d, J=8.4 Hz; 7.67-7.57 ppm (H- 32, H-32', H-35 and H-35', 4), m (in: 7.63 ppm (H-32 and H-32', 2), m (d), J=8.4 Hz; 7.605 ppm (H-35 and H-35', 2), m (d), J=7.2 Hz); 7.46 ppm (H-36 and H-36', 2), m (t), J=7.5 Hz; 7.39 ppm (H-37, 1), m (t), J=7.3 Hz; 7.14 ppm (H-22, 1), t, J=7.8 Hz; 6.81 ppm (H-23, 1), d, J=7.4 Hz; 6.78 ppm (H-21, 1), d, J=8.2 Hz; 5.05 ppm (H-11, 1), td, J=8.3 Hz and 6.3 Hz; 3.82 ppm (H-2, 3), s, 3.66 ppm (H-15, 2), m; 2.94-2.80 ppm (H-4a and H-7a, 2), m (in: 2.90 ppm (H-4a, 1), dd, J=14.9 Hz and 6.1 Hz; 2.845 ppm (H-7a, 1), dd, J=14.5 Hz and 6.3); 2.63-2.50 ppm (H-4b and
H-7b, 2), m (in: 2.58 ppm (H-7b, 1), dd, J=14.6 Hz and 6.8 Hz; 2.55 ppm (H-4b, 1), dd, J=15.0 Hz and 7.0 Hz); 2.50-2.35 ppm (H-9 and H-lOa, 2), m (in: 2.465 ppm (H-lOa, 1), m (ddd), i=\23 Hz, 7.6 Hz and 6.3 Hz; 2.40 ppm (H-9, 1), m, J-7.6 Hz); 2.03 ppm (H-8, 1), m (tt), J=8.9 Hz and 6.9 Hz, 1.81 ppm (H-12, 1), m (tt), J=8.2 Hz and 6.7 Hz; 1.77-1.45 ppm (H-13 and H-14, 4), m (in: 1.73 ppm (H-14a, 1), m; 1.70 ppm (H-14b, 1), m; 1.625 ppm (H-13a, 1), m; 1.60 ppm (H-13b, 1), m), 1.39 ppm (H-lOb, 1), dt, J=12.2 Hz and 8.6 Hz,
13C NMR (125.8 MHz): 166.50 ppm (C-29), 156.66 ppm (C-3), 145.72 ppm (C-33), 140.16 ppm (C-6 and C-34, 2); 130.20 ppm (C-31 and C-31 ', 2), 129.33 ppm (C-30), 129.04 ppm (C-36 and C-36', 2), 128.24 ppm (C-37), 127.39 ppm (C-35 and C-35', 2), 127.16 ppm (C-32 and C- 32', 2), 126.78 ppm (C-5), 126.37 ppm (C-22), 120.58 ppm (C-23), 108.45 ppm (C-21), 79.86 ppm (C-ll), 63.29 ppm (C-15), 55.65 ppm (C-2), 49.36 ppm (C-12), 40.96 ppm (C-8), 37.98 ppm (C-10), 33.76 ppm (C-9), 33.69 ppm (C-7), 30.77 ppm (C-14), 28.98 ppm (C-13), 25.88 ppm (C-4).
2k.) Preparation of [(lR,9aS)-5-methoxy-l-(3-oxopropyl)-2,3,3a,4,9,9a-hexahydro-lH- cyclopenta[b]naphth-2-yl] 4-phenylbenzoate (MPK-10)
MPK-9 MPK-10
: 456.59 M: 454.57
In an inert atmosphere 140 ml of oxalyl chloride is dissolved in 4.2 1 of dichloromethane. The solution is cooled to (-)-60°C and 227 ml of dimethyl sulfoxide in 1130 ml dichloromethane solution and then, after stirring 376 g of MPK-9 in 690 ml of dichloromethane solution are added. Stirring is continued at (-)-60°C. At the end of the reaction the mixture is quenched by the addition of 830 ml triethylamine. The mixture is agitated for 1 hour without cooling, then the temperature is elevated to 10°C and 1 M NaHS04 solution is added. The aqueous phase is extracted with dichloromethane, the united organic phase is washed with water, dried and evaporated. The crude product is purified first by chromatography on silica gel column using hexane: ethyl acetate mixture as eluent, then by crystallisation from toluene: hexane mixture.
Yield: 374 g (100 %) of white crystals. Mp: 94-96 °C. NMR data:
(CDC13), 1H NMR (500 MHz): 9.78 ppm (H-15, 1), t, J=1.3 Hz; 8.05 ppm (H-31 and H-31', 2), m (d), J=8.5 Hz; 7.68-7.57 ppm (H-32, H-32', H-35 and H-35', 4), m (in: 7.64 ppm (H-32 and H-32', 2), m (d), J=8.5 Hz; 7.61 ppm (H-35 and H-35', 2), m (d), J=7.0 Hz); 7.46 ppm (H-36 and H-36', 2), m (t), J=7.6 Hz; 7.39 ppm (H-37, 1), m (t), J=7.4 Hz; 7.15 ppm (H-22, 1), t, J=7.8 Hz, 6.82 ppm (H-23, 1), d, J=7.4 Hz; 6.78 ppm (H-21, 1), d, J=8.2 Hz, 5.02 ppm (H-ll, 1), td, J=8.3 Hz and 6.3 Hz; 3.82 ppm (H-2, 3), s; 2.935-2.79 ppm (H-4a and H-7a, 2), m (in: 2.865 ppm (H- 4a, 1), dd, J=14.9 Hz and 6.1 Hz; 2.835 ppm (H-7a, 1), dd, J=14.4 Hz and 6.3); 2.65-2.53 ppm (H-4b, H-7b and H-14, 4), m (in: 2.61 ppm (H-14, 2), ddd, J=7.6 Hz, 6.5 Hz and 1.1 Hz; 2.576 ppm (H-7b, 1), dd, J=14.5 Hz and 6.3 Hz; 2.568 ppm (H-4b, 1), dd, J=14.9 Hz and 6.5 Hz); 2.53- 2.36 ppm (H-9 and Η-10β, 2), m (in: 2.485 ppm (Η-10β, 1), ddd, J=12.1 Hz, 7.6 Hz and 6.4 Hz; 2.42 ppm (H-9, 1), m); 2.075-1.89 ppm (H-8 and H-13a, 2), m (in: 2.02 ppm (H-8, 1), m, 1.94 ppm (H-13a, 1), m); 1.85-1.73 ppm (H-12 and H-13b, 2), m (in: 1.80 ppm (H-14b, 1), m; 1.79 ppm (H-12, 1), m); 1.345 ppm (H-10a, 1), dt, J=12.2 Hz and 8.8 Hz, 13C NMR (125.8 MHz): 202.22 ppm (C-15), 166.33 ppm (C-29), 156.71 ppm (C-3), 145.85 ppm (C-33), 140.11 ppm (C- 34); 139.82 ppm (C-6), 130.20 ppm (C-31 and C-31 ', 2), 129.11 ppm (C-30), 129.06 ppm (C-36 and C-36', 2), 128.28 ppm (C-37), 127.40 ppm (C-35 and C-35', 2), 127.21 ppm (C-32 and C- 32', 2), 126.60 ppm (C-5), 126.46 ppm (C-22), 120.66 ppm (C-23), 108.54 ppm (C-21), 79.48 ppm (C-ll), 55.65 ppm (C-2), 48.70 ppm (C-12), 41.95 ppm (C-14), 40.79 ppm (C-8), 37.91 ppm (C-10), 33.53 ppm (C-9), 33.29 ppm (C-7), 25.73 ppm (C-4), 24.69 ppm (C-13).
211.) Preparation of [( 1 R,2R,9aS)- 1 -[(3 S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro- lH-cyclopenta[b]naphth-2-yl] 4-phenylbenzoate (PPB-TREP-14)
excess reagent
dlpent lzlnc
: 207.66
To 4.5 1 of distilled toluene in an inert atmosphere 7.5 g of MIB* catalyst and then 1800 ml of dipentylzinc are added. The mixture is agitated at room temperature. After 1 hour of agitation the solution of 300 g of MPK-10 in 1.5 1 of distilled toluene is added at room temperature and the mixture is stirred until the coupling reaction proceeds. Then, under intensive agitation, the reaction mixture is poured onto hydrochloric acid solution. Stirring is continued till complete decomposition of the zinc salts, then the product is extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution and then evaporated. The crude product is purified by gradient chromatography on silica gel column using toluene: tert- butyl methyl ether mixtures as eluent.
Yield: 300 g (86%) of yellow oil.
NMR data:
(CDC13), 1H NMR (500 MHz): 8.05 ppm (H-31 and H-31 \ 2), m (d), J=8.3 Hz; 7.68-7.53 ppm (H-32, H-32\ H-35 and H-35', 4), m (in: 7.63 ppm (H-32 and H-32', 2), m (d), J=8.3 Hz; 7.605 ppm (H-35 and H-35', 2), m (d), J=7.5 Hz), 7.46 ppm (H-36 and H-36', 2), m (t), J=7.6 Hz, 7.39 ppm (H-37, 1), m (t), J=7.3 Hz, 7.14 ppm (H-22, 1), t, J=7.8 Hz, 6.82 ppm (H-23, 1), d, J=7.4 Hz; 6.78 ppm (H-21, 1), d, J=8.2 Hz, 5.05 ppm (H-ll, 1), td, J=8.2 Hz and 6.4 Hz, 3.82 ppm (H-
2, 3), s, 3.61 ppm (H-15, 1), m; 2.955-2.80 ppm (H-4a and H-7a, 2), m (in: 2.905 ppm (H-4a, 1), dd, J=14.9 Hz and 6.1 Hz; 2.85 ppm (H-7a, 1), dd, J=14.5 Hz and 6.3), 2.66-2.51 ppm (H-4b and H-7b, 2), m (in: 2.585 ppm (H-7b, 1), dd, J=14.5 Hz and 6.8 Hz; 2.54 ppm (H-4b, 1), dd, J=15.1 Hz and 7.0 Hz), 2.51-2.35 ppm (H-9 and H-lOa, 2), m (in: 2.47 ppm (H-lOa, 1), ddd, J=12.3 Hz, 7.6 Hz and 6.4 Hz; 2.41 ppm (H-9, 1), m), 2.03 ppm (H-8, 1), m (tt), J=9.0 Hz and 6.8 Hz, 1.81 ppm (H-12, 1), m, 1.75-1.48 ppm (H-13 and H-14, 4), m (in: 1.675 ppm (H-13a, 1), m; 1.62 ppm (H-14a, 1), m; 1.59 ppm (H-13b, 1), m; 1.545 ppm (H-14b, 1), m); 1.48-1.33 ppm (H-lOb, H-16, H-17a and OH-15, 5), m (in: 1.43 ppm (H-16a, 1), m; 1.41 ppm (H-17a, 1), m; 1.40 ppm (H-16b, 1), m; 1.39 ppm (H-lOb, 1), m), 1.33-1.17 ppm (H-17b, H-18 and H-19, 5), m (in: 1.28 ppm (H- 19, 2), m; 1.27 ppm (H-17b, 1), m; 1.26 ppm (H-18, 2), m), 0.86 ppm (H-20, 3), m (t), J=6.8 Hz, 13C NMR (125.8 MHz): 166.46 ppm (C-29), 156.67 ppm (C-3), 145.70 ppm (C-33), 140.21 ppm/140.14 ppm (C-6/C-34), 130.20 ppm (C-31 and C-31 ', 2), 129.39 ppm (C-30), 129.04 ppm (C-36 and C-36', 2), 128.24 ppm (C-37), 127.40 ppm (C-35 and C-35', 2), 127.13 ppm (C-32 and C-32', 2), 126.82 ppm (C-5), 126.36 ppm (C-22), 120.60 ppm (C-23), 108.45 ppm (C-21), 79.83 ppm (C-l l), 73.13 ppm (C-15), 55.66 ppm (C-2), 49.41 ppm (C-12), 40.94 ppm (C-8), 38.03 ppm (C-10), 37.55 ppm (C-16), 35.11 ppm (C-14), 33.78 ppm (C-9), 33.67 ppm (C-7), 32.02 ppm (C-18), 28.53 ppm (C-13), 25.92 ppm (C-4), 25.43 ppm (C-17), 22.76 ppm (C-19), 14.16 ppm (C-20).
*MIB catalyst: (2S)-3-exo-(morpholino)isoborneol, M: 239.35, C14H25N02
Preparation of Dipentylzinc
To 550 g of vaseline 267 g of zinc-copper alloy (10% copper, 90% zinc) is added. In an inert atmosphere the mixture is heated to approx. 60°C, then agitation is started and the mixture is heated to 160°C. Under continuous reflux and intensive cooling the mixture of 188 ml of 1- pentyl iodide and 186 ml of 1-pentyl bromide is added. After the addition agitation is continued for 1 hour while keeping the temperature. The mixture is then cooled to approx. 60°C. The product is distilled off at an inner temperature of 110-150 °C under 0.5-1.5 mbar vacuum.
21.2) Preparation of [( 1 R,2R,9aS)- 1 -[(3 S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro- lH-cyclopenta[b]naphth-2-yl] 4-phenylbenzoate (PPB-TREP-14)
In 16 ml of dichloromethane 1.3 ml of Ti(OiPr)4 is dissolved and after cooling to
(-)70°C 1.1 ml (2.2 mmol) of pentylmagnesium bromide (2M solution in diethyl ether) is added to the mixture. In 4 ml of dichloromethane 100 mg (0.22 mmol) of MPK-10, 10 mg of (R)-(+)-l,l'-Bi(2-naphthol) and 0.4 ml of Ti(OiPr)4 are dissolved, the solution is cooled to 0/+5 °C and the pentylmagnesium bromide reagent solution is added to it. Stirring is continued at 0/+5 °C. At the end of the reaction 2 ml of 1 :1 hydrochloric acid-water mixture is added carefully. The phases are separated, the organic phase is washed with 5 ml of water, dried and evaporated. The crude product contains
0-20% 15-epi-PPB-TREP-14 isomer. The product is purified by chromatography on silica gel using hexane: ethyl acetate mixture as eluent.
Yield: 90 mg (77%) of yellow oil.
2m.) Preparation of
( 1 R,2R,3aS,9aS)- 1 -[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro- 1 H- cyclopenta[b]naphth-2-ol (TREP-14)
In 1 1 of tetrahydrofuran 250 g of PPB-TREP-14 is dissolved, to the solution 2.5 1 of methanol and 150 g of potassium carbonate are added and the mixture is stirred at 45 °C. At the end of the reaction the pH of the mixture is set to 2-4 with diluted phosphoric acid, the precipitated crystals are filtered off and washed with methanol. The filtrate solution is concentrated, to the
concentrated product solution ethyl acetate is added, the phases are separated, the aqueous phase is extracted with ethyl acetate, the united organic phase is washed with sodium chloride solution and evaporated. The crude product is purified by chromatography on silica gel column using hexane: ethyl acetate mixtures as eluent. The evaporated main fraction is crystallized in diisopropyl ether: hexane mixture.
Yield: 125 g (76 %) of white crystals. Mp: 71-72 °C.
Claims
Claims
1. Method for the preparation of treprostinil of formula I and its amorph salt forms, anhydrates, and monohydrates and polyhydrates of salts given with bases,
characterized in that,
a compound of the general formula XVII
XVII
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- group,
with the proviso that the R1 protective group must be selectively removable from R2 and R4, x represents 0 or 2 - is reacted with a compound of the general formula XVI
- where in the formula
R2 represents -(CH2)n , where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4 )alkylsilyl- or (C1-4 )alkyl-di(C6-10)arylsilyl- group and n stands for 1,2,3,4 -
al .) in the presence of Grignard reagent, and the resulting compound of the general formula XV
- where in the formula x, R1 and R2 have the meanings as defined above - is oxidized, the resulting compound of the general formula XIV
- where in the formula x, R1 and R2 have the meanings as defined above - is selectively reduced, or a2.) in the presence of chiral base and zinc salt, and
the compound of the general formula XIII. obtained in step al .) or a2.)
1
- where in the formula x, R and R have the meanings as defined above - is reacted with a compound suitable for the introduction of group R - where R represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group -, b.) the resulting compound of the general formula XII
R3
- where in the formula x, R1, R2 and R3 have the meanings as defined above- is subjected to intramolecular cyclisation,
c.) the resulting compound of the eneral formula XI
-where in the formula R1, R2 have the meanings as defined above, and in compound of formula Xa. x=0, in compound of formula Xb. x=2 -, is reduced,
e.) the resulting compound of the general formula IX
the R protective group is cleaved in acidic medium, g.) the resulting compound of the general formula VII
- where in the formula x, R2 and R4 have the meanings as defined above - hi.) in the case where x means 0, is reacted in Wittig reaction with the compound of the general formula
CH3-(CH2)4-CO-CH2-PO(OR6)2
- wherein R6 stands for C1-4 alkyl- or phenyl- group -, and the resulting compound of the general formula V
- where in the formula R2 and R4 have the meanings as defined above - is selectively reduced, and the R4 protective group of the resulting compound of the general formula IVa.
- where in the formula R2 and R4 have the meanings as defined above -, R4is removed, and the resulting compound of the general formula III
- where in the formula R has the meaning as defined above - is hydrogenated, or h2.) in the case where x means 2, is reacted in the presence of chiral catalyst with an organic metal reagent, and the protective group R4 of the resulting compound of the general formula IVb.
- where in the formula R2 and R4 have the meanings as defined above-, R4 is removed, i) the compound of the general formula II obtained in steps hi.) or h2.)
- where in the formula R2 has the meaning as defined above - is transformed by known method into treprostinil of formula I and if desired, into its salts given with bases.
2. The method as defined in Claim 1 , characterized in that as R1 protective group
methoxymethyl-, methoxyethoxymethyl- or tetrahydropyranyl- group, as R protective group methyl group, as R3 protective group a protective group containing silicium atom, preferably tert-butyldimethylsilyl group, as R4 protective group p-phenylbenzoyl group is applied.
3. Process as defined in Claim lal, characterized in that as Grignard reagent methyl-, ethyl-, propyl-, butyl-, cyclohexyl- magnesium bromide, preferably methylmagnesium bromide is applied.
4. Process as defined in Claim lal, characterized in that the oxidation of the compound of formula XV is carried out with pyridinium chlorochromate.
5. Process as defined in Claim lal, characterized in that the oxidation of the compound of formula XV is carried out by Swern oxidation.
6. Process as defined in Claim lal, characterized in that the reduction is carried out with borane compound, in the presence of chiral oxazaborolidine catalyst.
7. Process as defined in Claim 6, characterized in that as borane compound borane-dimethyl sulfide complex, catecholborane or borane-diethylaniline complex, preferably borane-dimethyl sulfide complex is applied.
Process as defined in Claim la2, characterized in that as chiral base chiral aminoalcohols diamines, preferably (+)-N-methylephedrine are applied.
9. Process as defined in Claim la2, characterized in that as zinc salt, zinc triflate is applied.
10. Process as defined in Claim lb, characterized in that the intramolecular cyclisation is carried out by Pauson-Khand cyclisation method.
11. Process as defined in Claim 10, characterized in that the Pauson -Khand cyclisation is carried out by using dicobalt octacarbonyl.
12. Process as defined in Claim 11 , characterized in that dicobalt octacarbonyl is applied in equimolar amount or less than equimolar or more than equimolar amounts.
13. Process as defined in Claims 10-12, characterized in that the reaction is carried out under carbon monoxide atmosphere.
14. Process as defined in Claims 10-13, characterized in that the reaction is carried out in ethyl acetate.
15. Process as defined in Claim 1 c, characterized in that for the hydrogenation of the compound of formula XI. as catalyst Pd/C or platinum oxide catalyst, preferably Pd/C catalyst is applied.
16. Process as defined in Claim Id, characterized in that the reduction of the compound of formula X is carried out with diisobutylaluminum hydride, lithium aluminum hydride, aluminum isopropylate or sodium borohydride, preferably sodium borohydride.
17. Process as defined in Claim le, characterized in that as compound suitable for the introduction of group R4, p-phenylbenzoyl chloride is applied.
18. Process as defined in Claim If, characterized in that the Rl protective group containing silicium atom is phenyldimethylsilyl-, tnethylsilyl-, triisopropylsilyl-, tert-butyldimethylsilyl- or tert-butyldiphenylsilyl- group.
19. The process as defined in Claim lg, characterized in that the oxidation of the compound
of formula VII is carried out under Swern conditions, or with TEMPO, or under Pfitzner-Moffat conditions.
20. Process according to Claim lhl , characterized in that the reduction of the compound of formula V. is carried out with a borane compound, in the presence of
oxazaborolidine catalyst.
21. Process as defined in Claim 20 characterized in that as borane compound catecholborane, borane-diethylaniline complex, borane-dimethyl sulfide complex, preferably borane-dimethyl sulfide complex is applied.
22. Process as defined in Claim lh2, characterized in that as organic metal reagent dipentylzinc or pentylmagnesium bromide are applied.
23. Process as defined in Claim lh2, characterized in that as chiral catalyst (2S)-3-exo- (morpholino)isoborneol is applied.
24. Process according to Claim li, characterized in that the hydrogenation of the compound of the general formula III. is carried out in the presence of catalyst.
25. Process according to Claim 24, characterized in that the applied catalyst is platinum oxide catalyst, Pd/C catalyst, preferably Pd/C catalyst.
26. Process according to claim 1 i, characterized in that the R4 protective group which contains silicium atom (phenyldimethylsilyl-, triethylsilyl-, triisopropylsilyl-, tert- butyldimethylsilyl- or tert-butyldiphenylsilyl- group), trityl-, methoxytrityl-, p-methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or Ct-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R2, and R1 must be selectively removable from R4.
27. Process according to claims li, characterized in that the cleveage of the R4 protective group is carried out by methanolysis, in the presence of base.
Process for the preparation of the amorph, anhydrate salts of treprostinil of formula I
given with bases, and the monohydrates and polyhydrates thereof
29. Process as defined in Claims 1 and 28 for the preparation of the salts of treprostinil of formula I given with bases, characterized in that as polar solvent C1-5 open-chain or branched organic alcohol, preferably ethanol is applied.
30. Process as defined in Claims 1 and 28 for the preparation of the salts of treprostinil of formula I given with bases, characterized in that as for base, the solventless organic or inorganic base which contains the cation of the desired salt is applied.
31. Process as defined in Claim 30 for the preparation of the salts of treprostinil of formula I given with bases, characterized in that as for base, an organic or inorganic base containing alkali metal or alkali earth-metal cation is applied.
32. Process as defined in Claim 31 for the preparation of the salts of treprostinil of formula I given with bases, characterized in that as for base sodium carbonate monohydrate, sodium hydrogen carbonate, sodium methylate, preferably sodium carbonate hydrate is applied.
33. Process as defined in Claims 1 and 28 for the preparation of the salts of treprostinil of formula I given with bases, characterized in that the reaction mixture is agitated in an inert atmosphere until salt formation proceeds.
34. Process as defined in Claims 1 and 28 for the preparation of the salts of treprostinil of
formula I given with bases, characterized in that as the organic solvent of the crystallisation an ether-, ester- or ketone-type solvent is applied.
35. Process as defined in Claims 1 and 28 for the preparation of the salts of treprostinil of formula I given with bases, characterized in that as ether-type solvent a branched or open-chain simple or mixed ether, preferably tert-butyl methyl ether is applied.
36. Process as defined in Claims 1 and 28 for the preparation of the monohydrate salts of treprostinil of formula I given with bases, characterized in that crystallisation is carried out at a temperature of 50°C - (- 40°C), preferably at room temperature.
37. Process as defined in Claim 36 for the preparation of the monohydrate salts of treprostinil of formula I. given with bases, characterized in that the crystals are dried at a temperature of 20- 50°C, in vacuum.
38. Process as defined in Claims 34 and 37 for the preparation of the monohydrate salts of treprostinil of formula I. given with bases, characterized in that the organic solvent of the crystallisation is an organic solvent which has been saturated with water.
39. Process as defined in Claims 34 and 37 for the preparation of the amorph salts of treprostinil of formula I given with bases, characterized in that the organic solvent of the crystallisation is a water-free organic solvent.
40. Process as defined in Claims 1 and 28 for the preparation of the anhydrate salts of treprostinil of formula I given with bases, characterized in that the crystals are dried at a temperature of 60-100°C, in vacuum.
41. Process as defined in Claims 1 and 28 for the preparation of the polyhydrate salts of treprostinil of formula I given with bases, characterized in that the crystals are kept under an atmosphere of 20-80% moisture content for at least 48 hours, or in the air for 5-10 days.
42. The compounds of the general formula III
- where in the formula
R represents -(CH2)n Y, where
Y stands for hydrogen atom, halogen atom, phenyl-, -OR5 or -COOR5 group, wherein
R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4 )alkylsilyl- or (C1-4)alkyl-di(C -1o)arylsilyl- group and n stands for 1,2,3,4 -, with the proviso that R5 in -COOR5 cannot stay for C alkyl.
The compounds of the general formula IV
- where in the formula
R2 represents -(CH2)n Y, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(C )alkylsilyl- or (CMialkyl-diiCe-^ rylsilyl- group, n stands for 1,2,3,4,
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, with the proviso that the R4 protective group must be
selectively removable from R2, and
the dotted line represents single or double bond.
44. Compounds of the general formula V
- where in the formula
R2 represents -(CH2)n Y, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means CM alkyl-, tetrahydropyranyl-, tri(Cu )alkylsilyl- or
group, n stands for 1,2,3,4 and
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R2.
The compounds of the above general formula VI
- where in the formula
R2 represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(C )alkylsilyl- or (Ci-4)alkyl-di(C6-io)arylsilyl-
group,
n stands for 1,2,3,4,
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl-group, with the proviso that the R4 protective group must be selectively removable from R , and
x represents 0 or 2.
The compound of the general formula VII
- where in the formula
R2 represents -(CH2)NY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(CM)alkylsilyl- or (CM)alkyl-di(C6-io)arylsilyl- group,
n stands for 1,2,3,4,
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or CM 3 acyl-group, with the proviso that the R4 protective group must be selectively removable from R2, and
x represents 0 or 2.
The compounds of the general formula VIII
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-,
R represents -(Ώ¼)ηΥ, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-1o)arylsilyl- group,
n stands for 1,2,3,4,
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or Q.o acyl- group, with the proviso that the R4 protective group must be selectively removable from R , and
x represents 0 or 2.
The compounds of the general formula ΓΧ
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-,
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(Ci-4)alkylsilyl- or (C1-4)alkyl-di(C6-i0)arylsilyl- group,
n stands for 1,2,3,4 and x represents 0 or 2.
49. The compounds of the eneral formula X
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl,- ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- group, with the proviso that the R protective group must be selectively removable from R and
R represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl- group,
n stands for 1,2,3,4 and x represents 0 or 2.
The compounds of the general formula XI
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-,
R represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1 -4)alkyl-di(C6-10)arylsilyl- group,
n stands for 1,2,3,4,
R3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or Ci-13 acyl- group,
and x represents 0 or 2.
51. The compounds of the general formula XII
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-,
ethoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl-
R2 represents -(CH2)„Y, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-io)a ylsilyl- group,
n stands for 1,2,3,4,
R represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, and x represents 0 or 2.
The compounds of the general formula XIII
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-,
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C )alkyl-di(C6-i0)arylsilyl- group,
n stands for 1,2,3,4 and x represents 0 or 2.
The compounds of the general formula XIV
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-,
R represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl- group,
n stands for 1,2,3,4 and x represents 0 or 2.
54. The compounds of the general formula XV
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- group, with the proviso that the R protective group must be selectively removable from R and
R2 represents -(CH2)nY, wherein
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (Ci-4)alkyl-di(C6-io)arylsilyl-
group,
n stands for 1,2,3,4 and x represents 0 or 2.
55. Sodium salt monohydrate of treprostinil of formula I.
56. Amorph sodium salt of treprostinil of formula I.
57. Sodium salt anhydrate of treprostinil of formula I.
58. Sodium salt polyhydrate of treprostinil of formula I (3-5 mol water content).
59. Treprostinil intermediates of the general formulae III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV and XV
- where in the formula
R1 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- group, with the proviso that the R1 protective group must be selectively removable from R2 and R4,
R2 represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR or -COOR group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(Ci-4)alkylsilyl- or (C1-4)alkyl-di(C6-10)arylsilyl- group,
n stands for 1,2,3,4,
R3 represents a protective group containing silicium atom, tetrahydropyranyl-, trityl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or CM 3 acyl- group,
R4 represents a protective group containing silicium atom, trityl-, methoxytrityl-, p- methoxybenzyl-, methoxymethyl-, ethoxymethyl-, methoxyethoxymethyl-, methylthiomethyl-, benzyloxymethyl- or C1-13 acyl- group, with the proviso that the R4 protective group must be selectively removable from R2,
x represents 0 or 2,
and the dotted line represents single or double bond, with the proviso that in compound of the general formula III Y cannot stay for nitrile or -COOR5, where R5 stays for C1-4 alkyl.
60. Process according to Claim 1 , characterized in that removal of the R2 group of the compound of the general formula II
II
-where in the formula
R represents -(CH2)nY, where
Y stands for hydrogen atom, halogen atom, phenyl-, nitrile-, -OR5 or -COOR5 group, wherein R5 means C1-4 alkyl-, tetrahydropyranyl-, tri(C1-4)alkylsilyl- or (C1 -4)alkyl-di(C6-1o)arylsilyl- group,
and n stands for 1,2,3,4,
is carried out with dodecanethiol in the presence of alkali halogenide.
Priority Applications (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP15787660.8A EP3204349A1 (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
| KR1020247009377A KR20240046264A (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
| JP2017518846A JP6820255B2 (en) | 2014-10-08 | 2015-09-28 | How to make treprostinil |
| CA2963844A CA2963844C (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
| BR112017007270-0A BR112017007270B1 (en) | 2014-10-08 | 2015-09-28 | COMPOUNDS AND TREPROSTINYL SODIUM SALT MONOHYDRATE AND PROCESSES FOR PREPARING THE SAME |
| SG11201702790YA SG11201702790YA (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
| RU2017115930A RU2709200C2 (en) | 2014-10-08 | 2015-09-28 | Method of producing treprostilinyl |
| MX2017004672A MX2017004672A (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil. |
| KR1020177012210A KR102651020B1 (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
| CN201580066416.6A CN107001221B (en) | 2014-10-08 | 2015-09-28 | Method for preparing treprostinil |
| US15/518,096 US10322990B2 (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
| AU2015329740A AU2015329740B2 (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
| IL251613A IL251613B (en) | 2014-10-08 | 2017-04-06 | Process for the preparation of treprostinil |
| US16/397,139 US11098001B2 (en) | 2014-10-08 | 2019-04-29 | Process for the preparation of treprostinil |
| US17/377,125 US11724979B2 (en) | 2014-10-08 | 2021-07-15 | Process for the preparation of treprostinil |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1400475A HU231186B1 (en) | 2014-10-08 | 2014-10-08 | Novel process for preparation of treprostinil and its salts |
| HUP1400475 | 2014-10-08 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US15/518,096 A-371-Of-International US10322990B2 (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
| US16/397,139 Division US11098001B2 (en) | 2014-10-08 | 2019-04-29 | Process for the preparation of treprostinil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016055819A1 true WO2016055819A1 (en) | 2016-04-14 |
Family
ID=89991608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2015/000065 WO2016055819A1 (en) | 2014-10-08 | 2015-09-28 | Process for the preparation of treprostinil |
Country Status (14)
| Country | Link |
|---|---|
| US (3) | US10322990B2 (en) |
| EP (1) | EP3204349A1 (en) |
| JP (2) | JP6820255B2 (en) |
| KR (2) | KR20240046264A (en) |
| CN (2) | CN107001221B (en) |
| AU (1) | AU2015329740B2 (en) |
| CA (1) | CA2963844C (en) |
| HU (2) | HU231186B1 (en) |
| IL (1) | IL251613B (en) |
| MX (1) | MX2017004672A (en) |
| RU (1) | RU2709200C2 (en) |
| SG (1) | SG11201702790YA (en) |
| TW (2) | TWI761299B (en) |
| WO (1) | WO2016055819A1 (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US9701616B2 (en) | 2015-06-17 | 2017-07-11 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US9776982B2 (en) | 2013-01-11 | 2017-10-03 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US9845305B2 (en) | 2013-01-11 | 2017-12-19 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| WO2017188644A3 (en) * | 2016-04-28 | 2018-01-18 | 연성정밀화학(주) | Method for preparing treprostinil and intermediate therefor |
| WO2018058124A1 (en) | 2016-09-26 | 2018-03-29 | United Therapeutics Corporation | Treprostinil prodrugs |
| US10556851B2 (en) | 2016-01-27 | 2020-02-11 | Emcure Pharmaceutical Limited | Process for preparation of prostacyclin derivatives |
| WO2020233588A1 (en) | 2019-05-21 | 2020-11-26 | 江苏众强药业有限公司 | New crystal form of treprostinil sodium salt and preparation method therefor |
| WO2021041320A1 (en) | 2019-08-23 | 2021-03-04 | United Therapeutics Corporation | Treprostinil prodrugs |
| WO2021211916A1 (en) | 2020-04-17 | 2021-10-21 | United Therapeutics Corporation | Treprostinil for use in the treatment of intersitial lung disease |
| WO2021252446A1 (en) | 2020-06-09 | 2021-12-16 | United Therapeutics Corporation | Fumaryl diketopiperidine prodrugs of treprostinil |
| WO2022132655A1 (en) | 2020-12-14 | 2022-06-23 | United Therapeutics Corporation | Methods of treating disease with treprostinil prodrugs |
| WO2022187352A1 (en) | 2021-03-03 | 2022-09-09 | United Therapeutics Corporation | A dry powder composition of trestinil and its prodrug thereof and further comprising comprising (e)-3,6-bis[4-(n-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (fdkp) |
| WO2023154705A1 (en) | 2022-02-08 | 2023-08-17 | United Therapeutics Corporation | Treprostinil iloprost combination therapy |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU231296B1 (en) * | 2018-03-09 | 2022-09-28 | Chinoin Zrt | Process for the preparation of the b polymorph form of treprostinil-diethanol-amine salt |
| KR102084044B1 (en) * | 2018-12-24 | 2020-03-03 | 주식회사 세미부스터 | Analysis method for silicon concentration in the phosphoric acid solution |
| US10781160B1 (en) | 2019-10-04 | 2020-09-22 | Chirogate International Inc. | Hexadecyl Treprostinil crystals and methods for preparation thereof |
| US11339110B2 (en) * | 2019-12-19 | 2022-05-24 | Chirogate International Inc. | Efficient crystallization process for preparing ultrapure Treprostinil and crystal prepared therefrom |
| US11447440B2 (en) * | 2020-10-29 | 2022-09-20 | Chirogate International Inc. | Treprostinil monohydrate crystals and methods for preparation thereof |
Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999021830A1 (en) | 1997-10-24 | 1999-05-06 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| WO1999025357A1 (en) | 1997-11-14 | 1999-05-27 | United Therapeutics Corporation | USE OF 9-DEOXY-2', 9-α-METHANO-3- OXA-4,5,6- TRINOR-3, 7-(1',3'-INTERPHENYLENE) -13,14-DIHYDRO- PROSTAGLANDIN F1 TO TREAT PERIPHERAL VASCULAR DISEASE |
| US6441245B1 (en) | 1997-10-24 | 2002-08-27 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| EP1628654A2 (en) | 2003-05-22 | 2006-03-01 | United Therapeutics Corporation | Compounds and methods for delivery of prostacyclin analogs |
| US20080013686A1 (en) | 2006-07-11 | 2008-01-17 | Canon Kabushiki Kaisha | Radiation imaging apparatus, driving method thereof and radiation imaging system |
| US20090163738A1 (en) * | 2007-12-17 | 2009-06-25 | United Therapeutics Corporation | Process to prepare treprostinil, the active ingredient in remodulin |
| WO2009137066A1 (en) * | 2008-05-08 | 2009-11-12 | United Therapeutics Corporation | Treprostinil monohydrate |
| WO2009158010A1 (en) | 2008-06-27 | 2009-12-30 | Concert Pharmaceuticals, Inc. | Prostacyclin analogs |
| WO2011153363A1 (en) | 2010-06-03 | 2011-12-08 | United Therapeutics Corporation | Treprostinil production |
| WO2012009816A1 (en) | 2010-07-22 | 2012-01-26 | Alphora Research Inc. | Synthesis of treprostinil and intermediates useful therein |
| WO2012088607A1 (en) | 2010-12-30 | 2012-07-05 | Alphora Research Inc. | Process for treprostinil salt preparation |
| US20130053581A1 (en) * | 2011-08-24 | 2013-02-28 | Chirogate International Inc. | Intermediates for the synthesis of benzindene prostaglandins and preparations thereof |
| WO2013174848A2 (en) * | 2012-05-23 | 2013-11-28 | Scipharm Sàrl | Improved process for the preparation of treprostinil and derivatives thereof |
| US20140275616A1 (en) * | 2013-03-15 | 2014-09-18 | United Therapeutics Corporation | Salts of treprostinil |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4338457A (en) | 1980-02-28 | 1982-07-06 | The Upjohn Company | Composition and process |
| CA1313670C (en) | 1980-02-28 | 1993-02-16 | Robert Charles Kelly | Carbacyclin analogs |
| CN102040618B (en) | 2009-04-30 | 2013-09-04 | 上海天伟生物制药有限公司 | Preparation method and relevant intermediate of PGF2a analogue |
| WO2012066607A1 (en) | 2010-11-19 | 2012-05-24 | 島産業株式会社 | Drying volume reduction processing device |
| EP2495235B1 (en) * | 2011-03-04 | 2015-08-05 | Newchem S.p.A. | Process for the synthesis of prostaglandins and intermediates thereof |
| CN103193627B (en) * | 2012-01-10 | 2016-04-20 | 上海天伟生物制药有限公司 | Crystal formation of a kind of prostaglandin analogue and its production and use |
| BR112015013085A2 (en) * | 2012-12-07 | 2017-07-11 | Cayman Chemical Co Inc | synthesis methods of a prostacyclin analog |
| ES2805367T3 (en) * | 2013-01-11 | 2021-02-11 | Corsair Pharma Inc | Treprostinil prodrugs |
| WO2016010538A1 (en) * | 2014-07-16 | 2016-01-21 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
-
2014
- 2014-10-08 HU HU1400475A patent/HU231186B1/en unknown
- 2014-10-08 HU HU1900346A patent/HU231184B1/en unknown
-
2015
- 2015-09-28 EP EP15787660.8A patent/EP3204349A1/en active Pending
- 2015-09-28 KR KR1020247009377A patent/KR20240046264A/en active Search and Examination
- 2015-09-28 JP JP2017518846A patent/JP6820255B2/en active Active
- 2015-09-28 CN CN201580066416.6A patent/CN107001221B/en active Active
- 2015-09-28 SG SG11201702790YA patent/SG11201702790YA/en unknown
- 2015-09-28 AU AU2015329740A patent/AU2015329740B2/en active Active
- 2015-09-28 US US15/518,096 patent/US10322990B2/en active Active
- 2015-09-28 WO PCT/HU2015/000065 patent/WO2016055819A1/en active Application Filing
- 2015-09-28 CA CA2963844A patent/CA2963844C/en active Active
- 2015-09-28 KR KR1020177012210A patent/KR102651020B1/en active IP Right Grant
- 2015-09-28 CN CN202110561010.2A patent/CN113292419A/en active Pending
- 2015-09-28 MX MX2017004672A patent/MX2017004672A/en unknown
- 2015-09-28 RU RU2017115930A patent/RU2709200C2/en active
- 2015-10-06 TW TW104132764A patent/TWI761299B/en active
- 2015-10-06 TW TW108142477A patent/TWI761731B/en active
-
2017
- 2017-04-06 IL IL251613A patent/IL251613B/en active IP Right Grant
-
2019
- 2019-04-29 US US16/397,139 patent/US11098001B2/en active Active
- 2019-09-11 JP JP2019165225A patent/JP6898401B2/en active Active
-
2021
- 2021-07-15 US US17/377,125 patent/US11724979B2/en active Active
Patent Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999021830A1 (en) | 1997-10-24 | 1999-05-06 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| US6441245B1 (en) | 1997-10-24 | 2002-08-27 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| WO1999025357A1 (en) | 1997-11-14 | 1999-05-27 | United Therapeutics Corporation | USE OF 9-DEOXY-2', 9-α-METHANO-3- OXA-4,5,6- TRINOR-3, 7-(1',3'-INTERPHENYLENE) -13,14-DIHYDRO- PROSTAGLANDIN F1 TO TREAT PERIPHERAL VASCULAR DISEASE |
| EP1628654A2 (en) | 2003-05-22 | 2006-03-01 | United Therapeutics Corporation | Compounds and methods for delivery of prostacyclin analogs |
| US20080013686A1 (en) | 2006-07-11 | 2008-01-17 | Canon Kabushiki Kaisha | Radiation imaging apparatus, driving method thereof and radiation imaging system |
| US20090163738A1 (en) * | 2007-12-17 | 2009-06-25 | United Therapeutics Corporation | Process to prepare treprostinil, the active ingredient in remodulin |
| WO2009078965A1 (en) | 2007-12-17 | 2009-06-25 | United Therapeutics Corporation | An improved process to prepare treprostinil, the active ingredient in remodulin |
| WO2009137066A1 (en) * | 2008-05-08 | 2009-11-12 | United Therapeutics Corporation | Treprostinil monohydrate |
| WO2009158010A1 (en) | 2008-06-27 | 2009-12-30 | Concert Pharmaceuticals, Inc. | Prostacyclin analogs |
| WO2011153363A1 (en) | 2010-06-03 | 2011-12-08 | United Therapeutics Corporation | Treprostinil production |
| WO2012009816A1 (en) | 2010-07-22 | 2012-01-26 | Alphora Research Inc. | Synthesis of treprostinil and intermediates useful therein |
| WO2012088607A1 (en) | 2010-12-30 | 2012-07-05 | Alphora Research Inc. | Process for treprostinil salt preparation |
| US20130053581A1 (en) * | 2011-08-24 | 2013-02-28 | Chirogate International Inc. | Intermediates for the synthesis of benzindene prostaglandins and preparations thereof |
| WO2013174848A2 (en) * | 2012-05-23 | 2013-11-28 | Scipharm Sàrl | Improved process for the preparation of treprostinil and derivatives thereof |
| EP2674413A1 (en) * | 2012-06-15 | 2013-12-18 | SciPharm SàRL | Process for the preparation of treprostinil and derivatives thereof |
| US20140275616A1 (en) * | 2013-03-15 | 2014-09-18 | United Therapeutics Corporation | Salts of treprostinil |
Non-Patent Citations (4)
| Title |
|---|
| "Pulmonary Arterial Hypertension", DRUGS, vol. 72, no. 18, 2012, pages 2351 - 2363 |
| DRUGS OF THE FUTURE, vol. 26, no. 4, 2001, pages 364 - 374 |
| R.M. MORIARTY ET.AL.: "The intramolecular asymmetric Paulson-Khand cyclization as a novel and general stereoselective route to benzindene prostacyclins: synthesis of UT-15 (Treprostinil)", J. ORG. CHEM., vol. 69, 2004, pages 1890 - 1902, XP002753208 * |
| SORBERA L A ET AL: "UT-15 TREATMENT OF PULMONARY HYPERTENSION TREATMENT OF PERIPHERAL VASCULAR DISEASE", DRUGS OF THE FUTURE, PROUS SCIENCE, ES, vol. 26, no. 4, 1 January 2001 (2001-01-01), pages 364 - 374, XP008045991, ISSN: 0377-8282, DOI: 10.1358/DOF.2001.026.04.618809 * |
Cited By (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11505535B2 (en) | 2013-01-11 | 2022-11-22 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US9845305B2 (en) | 2013-01-11 | 2017-12-19 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US9776982B2 (en) | 2013-01-11 | 2017-10-03 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US11958822B2 (en) | 2013-01-11 | 2024-04-16 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US11339139B2 (en) | 2013-01-11 | 2022-05-24 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US11046666B2 (en) | 2013-01-11 | 2021-06-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US10450290B2 (en) | 2013-01-11 | 2019-10-22 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US10752605B2 (en) | 2013-01-11 | 2020-08-25 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US10344012B2 (en) | 2013-01-11 | 2019-07-09 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US10988435B2 (en) | 2015-06-17 | 2021-04-27 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US11802105B2 (en) | 2015-06-17 | 2023-10-31 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US10246403B2 (en) | 2015-06-17 | 2019-04-02 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US10464877B2 (en) | 2015-06-17 | 2019-11-05 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US11407707B2 (en) | 2015-06-17 | 2022-08-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US10464878B2 (en) | 2015-06-17 | 2019-11-05 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US10703706B2 (en) | 2015-06-17 | 2020-07-07 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US10053414B2 (en) | 2015-06-17 | 2018-08-21 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US10759733B2 (en) | 2015-06-17 | 2020-09-01 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US11034645B2 (en) | 2015-06-17 | 2021-06-15 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US11866402B2 (en) | 2015-06-17 | 2024-01-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US9701616B2 (en) | 2015-06-17 | 2017-07-11 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US9957220B2 (en) | 2015-06-17 | 2018-05-01 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US10556851B2 (en) | 2016-01-27 | 2020-02-11 | Emcure Pharmaceutical Limited | Process for preparation of prostacyclin derivatives |
| WO2017188644A3 (en) * | 2016-04-28 | 2018-01-18 | 연성정밀화학(주) | Method for preparing treprostinil and intermediate therefor |
| CN109071406A (en) * | 2016-04-28 | 2018-12-21 | 研成精密化学株式会社 | Prepare the method for treprostinil and the intermediate for it |
| US10800737B2 (en) | 2016-04-28 | 2020-10-13 | Yonsung Fine Chemical Co., Ltd. | Method for preparing treprostinil and intermediate therefor |
| JP2019514911A (en) * | 2016-04-28 | 2019-06-06 | ヨンスン ファイン ケミカル カンパニー，リミテッド | Method for producing treprostinil and intermediate therefor |
| CN109071406B (en) * | 2016-04-28 | 2021-05-04 | 研成精密化学株式会社 | Methods of preparing treprostinil and intermediates therefor |
| WO2018058124A1 (en) | 2016-09-26 | 2018-03-29 | United Therapeutics Corporation | Treprostinil prodrugs |
| US11672775B2 (en) | 2016-09-26 | 2023-06-13 | United Therapeutics Corporation | Treprostinil prodrugs |
| WO2020233588A1 (en) | 2019-05-21 | 2020-11-26 | 江苏众强药业有限公司 | New crystal form of treprostinil sodium salt and preparation method therefor |
| EP3981759A4 (en) * | 2019-05-21 | 2023-07-19 | Jiangsu Forefront Pharmaceutical Co., Ltd. | New crystal form of treprostinil sodium salt and preparation method therefor |
| US11634443B2 (en) | 2019-08-23 | 2023-04-25 | United Therapeutics Corporation | Treprostinil prodrugs |
| WO2021041320A1 (en) | 2019-08-23 | 2021-03-04 | United Therapeutics Corporation | Treprostinil prodrugs |
| US20210330621A1 (en) | 2020-04-17 | 2021-10-28 | United Therapeutics Corporation | Treatment for interstitial lung disease |
| WO2021211916A1 (en) | 2020-04-17 | 2021-10-21 | United Therapeutics Corporation | Treprostinil for use in the treatment of intersitial lung disease |
| US11826327B2 (en) | 2020-04-17 | 2023-11-28 | United Therapeutics Corporation | Treatment for interstitial lung disease |
| WO2021252446A1 (en) | 2020-06-09 | 2021-12-16 | United Therapeutics Corporation | Fumaryl diketopiperidine prodrugs of treprostinil |
| US11793780B2 (en) | 2020-06-09 | 2023-10-24 | United Therapeutics Corporation | Prodrugs of treprosiinil |
| US11826328B2 (en) | 2020-12-14 | 2023-11-28 | United Therapeutics Corporation | Stable treprostinil prodrugs |
| WO2022132655A1 (en) | 2020-12-14 | 2022-06-23 | United Therapeutics Corporation | Methods of treating disease with treprostinil prodrugs |
| WO2022187352A1 (en) | 2021-03-03 | 2022-09-09 | United Therapeutics Corporation | A dry powder composition of trestinil and its prodrug thereof and further comprising comprising (e)-3,6-bis[4-(n-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (fdkp) |
| WO2023154705A1 (en) | 2022-02-08 | 2023-08-17 | United Therapeutics Corporation | Treprostinil iloprost combination therapy |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2015329740B2 (en) | Process for the preparation of treprostinil | |
| EP3440065B1 (en) | Process for the preparation of optically active beraprost | |
| WO2014094511A1 (en) | Intermediates for synthesizing treprostinil and preparation method thereof as well as the preparation method of treprostinil thereby | |
| US4298537A (en) | Process for producing steroid compounds having an oxo group in the side chain | |
| BR112017007270B1 (en) | COMPOUNDS AND TREPROSTINYL SODIUM SALT MONOHYDRATE AND PROCESSES FOR PREPARING THE SAME | |
| US6797832B1 (en) | Process for the production of 5-oxy-7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylic acid esters | |
| KR20210005627A (en) | Manufacturing method of Ilofrost | |
| JP4366013B2 (en) | Synthetic intermediate compound of A ring part of vitamin D derivative having substituent at 2-position | |
| JP3410492B2 (en) | 7-Octin-1-ene derivative and method for producing the same | |
| JP2001247557A (en) | Method of producing 5-oxy-7-oxabicyclo[4.1.0]hept-3-ene-3- carboxylic acid ester | |
| AU2002300302B2 (en) | Stereoselective synthesis of 24-hydroxylated compounds useful for the preparation of aminosterols, vitamin D analogs, and other compounds | |
| KR101014890B1 (en) | Novel cyclic compounds and process for preparing them | |
| Stiasni | Synthetic studies toward the total synthesis of berkelic acid and lytophilippine A | |
| JPH06321850A (en) | (2s,4ar,6s,8s,8as)-1,2,4a,5,6,7,8,8a-octahydro-2methyl-6-substituted alkenynaphthalene derivative | |
| JPH06220039A (en) | Production of optically active compound | |
| JPS6254789B2 (en) | ||
| JPH06228124A (en) | Production of optically active compound | |
| JPH06228125A (en) | Production of optically active compound | |
| JPH07101905A (en) | Production of carboxylic acid ester derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15787660 Country of ref document: EP Kind code of ref document: A1 |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 11201702790Y Country of ref document: SG |
|
| ENP | Entry into the national phase |
Ref document number: 2963844 Country of ref document: CA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 251613 Country of ref document: IL |
|
| ENP | Entry into the national phase |
Ref document number: 2017518846 Country of ref document: JP Kind code of ref document: A |
|
| WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2017/004672 Country of ref document: MX |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| REEP | Request for entry into the european phase |
Ref document number: 2015787660 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 15518096 Country of ref document: US Ref document number: 2015787660 Country of ref document: EP |
|
| REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112017007270 Country of ref document: BR |
|
| ENP | Entry into the national phase |
Ref document number: 20177012210 Country of ref document: KR Kind code of ref document: A |
|
| ENP | Entry into the national phase |
Ref document number: 2017115930 Country of ref document: RU Kind code of ref document: A |
|
| ENP | Entry into the national phase |
Ref document number: 2015329740 Country of ref document: AU Date of ref document: 20150928 Kind code of ref document: A |
|
| ENP | Entry into the national phase |
Ref document number: 112017007270 Country of ref document: BR Kind code of ref document: A2 Effective date: 20170407 |