CN107963962A - 制备曲前列环素及其衍生物的改进方法 - Google Patents
制备曲前列环素及其衍生物的改进方法 Download PDFInfo
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- CN107963962A CN107963962A CN201711097647.0A CN201711097647A CN107963962A CN 107963962 A CN107963962 A CN 107963962A CN 201711097647 A CN201711097647 A CN 201711097647A CN 107963962 A CN107963962 A CN 107963962A
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- Prior art keywords
- hexane
- general formula
- ethyl acetate
- compound
- reaction
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- 238000000034 method Methods 0.000 title abstract description 35
- 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 abstract description 16
- 229960005032 treprostinil Drugs 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- -1 allyloxy benzaldehyde Chemical compound 0.000 claims abstract description 25
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 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 14
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 7
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 abstract description 24
- 230000002255 enzymatic effect Effects 0.000 abstract description 9
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 abstract description 8
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002243 precursor Substances 0.000 abstract description 4
- 125000001246 bromo group Chemical group Br* 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 127
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
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- 239000000203 mixture Substances 0.000 description 18
- 239000012043 crude product Substances 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 12
- 229910052740 iodine Inorganic materials 0.000 description 12
- 229910052801 chlorine Inorganic materials 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 101710098556 Lipase A Proteins 0.000 description 9
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- 102100026001 Lysosomal acid lipase/cholesteryl ester hydrolase Human genes 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
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- 150000002431 hydrogen Chemical class 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 235000019421 lipase Nutrition 0.000 description 7
- 0 CCCCC(CCCC#CCC1C(CCC)=C(*)C(*)=CC1*)C** Chemical compound CCCCC(CCCC#CCC1C(CCC)=C(*)C(*)=CC1*)C** 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
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- 229960001866 silicon dioxide Drugs 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 241001251200 Agelas Species 0.000 description 5
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- 238000011068 loading method Methods 0.000 description 5
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical class COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000006647 Pauson-Khand annulation reaction Methods 0.000 description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000007872 degassing Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 229930015698 phenylpropene Natural products 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003815 prostacyclins Chemical class 0.000 description 2
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- KXYGKDBONOVZOM-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene Chemical compound C1=CC=CC2=C3CC=CC3=CC=C21 KXYGKDBONOVZOM-UHFFFAOYSA-N 0.000 description 1
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
- SSZWWUDQMAHNAQ-UHFFFAOYSA-N 3-chloropropane-1,2-diol Chemical compound OCC(O)CCl SSZWWUDQMAHNAQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PIKQUFBEAHAJLP-UHFFFAOYSA-N C=CCOc(cc1)cc(C=O)c1Br Chemical compound C=CCOc(cc1)cc(C=O)c1Br PIKQUFBEAHAJLP-UHFFFAOYSA-N 0.000 description 1
- HARXRCYVYODDLB-UHFFFAOYSA-N C=CCc1cc([Br]=C)c(C=O)cc1O Chemical compound C=CCc1cc([Br]=C)c(C=O)cc1O HARXRCYVYODDLB-UHFFFAOYSA-N 0.000 description 1
- JPKHYFYNBBCKCU-UHFFFAOYSA-N CCCc(c(C=O)c(cc1)Br)c1O Chemical compound CCCc(c(C=O)c(cc1)Br)c1O JPKHYFYNBBCKCU-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 1
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical group O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 1
- 241000222175 Diutina rugosa Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- UMYVESYOFCWRIW-UHFFFAOYSA-N cobalt;methanone Chemical compound O=C=[Co] UMYVESYOFCWRIW-UHFFFAOYSA-N 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- HJWLCRVIBGQPNF-UHFFFAOYSA-N prop-2-enylbenzene Chemical compound C=CCC1=CC=CC=C1 HJWLCRVIBGQPNF-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
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- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- 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
- C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
- C07C47/565—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups all hydroxy groups bound to the ring
-
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Abstract
描述了制备曲前列环素及其衍生物的方法。与现有技术相比,这种方法利用了用于制备这些化合物的关键中间体的易于扩大规模的酶促拆分。所述方法超过现有方法的另一显著改进为5‑烯丙氧基‑苯甲醛前体的区域选择性克莱森重排反应,这由2位的溴取代基促进。
Description
发明领域
本发明涉及用于生产曲前列环素的更短更方便的方法以及可用于该方法的新的中间体。所述方法的关键特征包括烯丙氧基苯甲醛前体的区域选择性克莱森重排反应;非立体选择性的分子内Pauson-Khand环化期间携带炔烃的侧链中醇部分的叔丁基二甲基硅烷基(TBDMS)保护;以及两种非对映的后期中间体的酶动力学拆分和随后的色谱分离。这种应用的方法提供了具有超过99%非对映体纯度的苯并茚前列环素曲前列环素。
发明背景
曲前列环素为前列环素(PGI2)的合成类似物,显示用于肺动脉高压(PAH)的治疗。曲前列环素作用的主要药理学作用机制为肺动脉和全身性动脉血管床的直接的血管舒张和血小板凝集的抑制。
US6700025公开了前列环素衍生物特别是曲前列环素的立体选择性合成的方法。然而,这一方法和其他已知的方法涉及大量的合成步骤和色谱纯化。本发明的目的为发现更加实用的方法,所述方法涉及更少的步骤和色谱纯化,以及通过酶促手段的关键中间体的高度非对映选择性拆分,酶促手段使得该方法更适用于扩大规模。
发明概述
本发明涉及用于制备曲前列环素及其衍生物的方法,以及通过涉及使用合适的脂肪酶和合适的酰化剂的动力学酶促拆分步骤的方法产生的中间体。本发明也涉及曲前列环素合成期间所制备的中间体(诸如通式4a、5、8、9、10、11’、12’、13a、14a、15a、16a、16和17的化合物)的新合成。而且,本发明涉及经由烯丙氧基苯甲醛前体(通式V的化合物)的克莱森重排反应的烯丙基苯甲醛中间体的制备,烯丙氧基苯甲醛前体由于卤素原子引入到烯丙氧基的对位而具有增强的区域选择性。而且,本发明涉及使用用于C-11侧链的非苄醇部分的甲硅烷基保护基。
发明详述
在一实施方案中,本发明涉及经由克莱森重排反应将通式V的化合物
转化为下列通式VI的化合物
其中X与Y彼此独立地为Br、I、Cl、F或H;优选地,X为Br而Y为H。
由于区域选择性克莱森重排反应,不需要通过色谱法或蒸馏法分离区域异构体。所需的区域异构体可通过重结晶获得。
在本发明的另一实施方案中,获得作为中间体的通式VII的化合物
其中X与Y如上文所定义的;其中PG1为苯酚部分的保护基,诸如甲基、甲氧基甲基、苄氧基甲基、甲氧基乙氧基甲基、苄基、4-甲氧基苄基、2,6-二氯苄基、3,4-二氯苄基;-CH2C(O)-ORx或-CH2CH2ORx。优选地PG1为苄基。Rx为C1-4烷基或任选取代的苄基。
烷基指饱和的直链(无支链的)或支链的烃链。个体基团的代表性实例为甲基;乙基;正丙基;异丙基(1-甲基乙基);正丁基;1-甲基丙基;异丁基(2-甲基丙基);仲丁基(1-甲基丙基)和叔丁基(1,1-二甲基乙基)。
在本发明的另一实施方案中,获得下列结构VIII的中间体,其作为在非立体选择性的分子内Pauson-Khand环化中的反应物
其中X,Y与PG1如上文所定义的;其中PG2为THP或甲硅烷基醇保护基-SiR1R2R3,其中R1、R2、R3彼此独立地选自甲基、异丙基、叔丁基和苯基,优选地R1和R2为甲基,R3为叔丁基;或R1、R2和R3为异丙基;最优选地R1和R2为甲基,R3为叔丁基。
本发明的另一实施方案涉及用氢气和合适的催化剂将通式IXa的化合物(两种立体异构体的混合物)
还原为下列通式X与XI的化合物混合物(两种非对映异构体的混合物)
其中X、Y、PG1与PG2如上文所定义的,并且其中Ra为H、OH、-ORx、-O-PG1、Br、I、Cl、F、-OAc、-OPiv,或-OCORy、-OCOORy、-SRy或-SO2Ry、并且其中Ry为C1-4烷基或芳基。
芳基指具有至少一个芳香环的单环的、双环的或三环的碳环。典型的实例包括苯基,萘基,二氢茚基(2,3-二氢茚基),1,2,3,4-四氢萘基和芴基。
本发明的另一实施方案涉及使用合适的脂肪酶和合适的酰化剂将下列通式XII和XIII的化合物混合物酶促拆分为下列通式XIV和XV的化合物混合物:
其中PG2如上文所定义的;W选自H、-CH2CN、-CH2COR4、-CH2CONR1R2和-CH2COSR3;并且其中
R1和R2彼此独立地选自甲基、乙基、异丙基、正丁基、吗啉基(morphinyl)、哌啶基和吡咯烷基;以及
R3为甲基、乙基、正丙基、异丙基、正丁基、异丁基或苯基;以及
R4为-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-O(CH2)3CH3、-OCH2CH(CH3)2或-OCH2-Ph;
其中PG2和W如上文所定义的,并且R为酰基,例如乙酰基、乙酰、丙酰基、苯甲酰基或新戊酰基。
优选地,PG2为TBDMS,R为乙酰基,W为-CH2-CN、-CH2COOH、或-CH2COORx,其中Rx为C1-4烷基或苄基。
优选地,在适当的酰化剂存在的情况下,在适当的溶剂中,例如在C5-C8烷烃或烷基醚中,使用合适的脂肪酶通过酶促酰化作用进行上述转化,该脂肪酶例如来自Aspergillus niger的脂肪酶(脂肪酶AP6),来自Candida rugosa的脂肪酶(CCL),来自猪胰腺的脂肪酶(PPL),脂肪酶Amano AK,脂肪酶Amano PS30,。
最优选地,用于以上转化的脂肪酶为脂肪酶Amano AK和脂肪酶Amano PS30。优选的酰化剂为乙酸乙烯酯并且优选的溶剂为己烷或庚烷。
优选地,在以上的转化中,通过诸如色谱法或结晶等合适的手段将酰化产物与非酰化产物分离,以便产生非对映体纯和对映体纯形式的酰化产物。
非对映体纯意指所示的并随后使酰化产物与非酰化产物分离的酶促酰化作用产生具有>99%纯度的由以上通式所表示的酰化的非对映异构体。将产物通过填充有能够分离对映异构体的固定相的HPLC柱来确定纯度水平,其中>99%的上述非对映异构体作为单一的对映体纯和非对映体纯的化合物离开柱。
本发明也涉及利用下列反应方案(方案1-3)制备曲前列环素的方法。
方案1:2-烯丙基-3-苄氧基-6-溴-苯甲醛(5)的制备
方案2:(S)-叔丁基-(1-丁-3-炔基-己氧基)-二甲基-硅烷(10)的制备
方案3:曲前列环素的制备(18)
本发明的另一实施方案涉及通式I、通式II、通式IIb、通式IIIb、或通式IVb的中间体化合物
其中
X与Y彼此独立地选自H、F、Cl、Br、I和苄基;以及
PG1选自甲基、甲氧基甲基、苄氧基甲基、甲氧基乙氧基甲基、苄基、4-甲氧基苄基、2,6-二氯苄基、3,4-二氯苄基;-CH2COOH、-CH2COORx和-CH2CH2OPG2;以及
PG2为THP、SiR1R2R3或-CH2ORx;以及
R1、R2和R3彼此独立地选自甲基、异丙基、叔丁基和苯基;
Ra为氢、羟基-ORx、-OCOORx、-OSO2Rx、Cl、Br、F、I、-SRx或-SO2Rx;
Rx为C1-4烷基或芳基;以及
其中X或Y中至少一个不是H。
本发明的另一实施方案涉及如上文所述的通式I、通式II、通式IIb、通式IIIb或通式IVb的化合物,其中X与Y彼此独立地选自H、Br或Cl;以及X或Y中至少一个不是H。
本发明的另一实施方案涉及如上文所述的通式I、通式II、通式IIb、通式IIIb或通式IVb的化合物,其中X为Br或Cl;Y为H,优选地X为Br。
本发明的另一实施方案涉及如上文所述的通式I、通式II、通式IIb、通式IIIb或通式IVb的化合物,其中PG2为THP或TBDMS,优选地PG2为TBDMS。
本发明的另一实施方案涉及通式I、通式II、通式IIb、通式IIIb或通式IVb的中间体化合物
其中
X与Y彼此独立地选自H、F、Cl、Br、I和苄基;以及
PG1选自甲基、甲氧基甲基、苄氧基甲基、甲氧基乙氧基甲基、苄基、4-甲氧基苄基、2,6-二氯基苄基、3,4-二氯苄基;-CH2COOH、-CH2COORx和-CH2CH2OPG2;以及
PG2为TBMDS;以及
Ra为氢、羟基-ORx、-OCOORx、-OSO2Rx、Cl、Br、F、I、-SRx或-SO2Rx;
Rx为C1-4烷基或芳基;以及
其中X或Y中至少一个不是H。
本发明的另一实施方案涉及通式I或通式II的化合物
其中
X与Y彼此独立地选自H、F、Cl、Br、I和苄基;以及
PG1选自甲基、甲氧基甲基、苄氧基甲基、甲氧基乙氧基甲基、苄基、4-甲氧基苄基、2,6-二氯苄基、3,4-二氯苄基;-CH2COOH、-CH2COORx和-CH2CH2OPG2;以及
PG2为THP、SiR1R2R3或-CH2ORx;以及
R1、R2和R3彼此独立地选自甲基、异丙基、叔丁基和苯基;
Ra为氢,羟基-ORx、-OCOORx、-OSO2Rx、Cl、Br、F、I、-SRx或-SO2Rx;
Rx为C1-4烷基或芳基;以及
其中X或Y中至少一个不是H。
本发明的另一实施方案涉及用于制备通式(II)化合物的方法,其包括下列步骤:
其中
X、Y、Ra、PG1和PG2如以上所定义的。
本发明的另一实施方案涉及如以上所述的方法,其中PG2为TBDMS。
本发明的另一实施方案涉及如以上所述的方法,其中Ra为羟基。
本发明的另一实施方案涉及如以上所述的方法,其中X为Br,Y为氢,PG1为苄基,PG2为TBDMS;以及Ra为羟基。
本发明的另一实施方案涉及用于制备通式IV的化合物的方法,其包括以下步骤:
a)氢化和还原通式II的化合物以获得通式III的外消旋化合物;
b)在溶剂的存在下,使通式III的外消旋化合物与脂肪酶AK接触;以及
c)获得光学纯的化合物IV;
其中
PG2为THP或TBDMS,优选地PG2为TBDMS。
本发明的另一实施方案涉及如上文所述的方法,其中所述溶剂选自乙酸乙烯酯、己烷、庚烷和氯仿。
本发明的另一实施方案涉及如上文所述的方法,其中在约8-12的pH值,优选在约9-10的pH值进行所述氢化。
下列定义的主题被认为是本发明的实施方案:
1.通式I、通式II、通式IIb、通式IIIb或通式IVb的化合物:
其中
X与Y彼此独立地选自H、F、Cl、Br、I和苄基;以及
PG1选自甲基、甲氧基甲基、苄氧基甲基、甲氧基乙氧基甲基、苄基、4-甲氧基苄基、2,6-二氯苄基、3,4-二氯苄基;-CH2COOH、-CH2COORx和-CH2CH2OPG2;以及
PG2为TBDMS;以及
Ra为氢、羟基-ORx、-OCOORx、-OSO2Rx、Cl、Br、F、I、-SRx或-SO2Rx;
Rx为C1-4烷基或芳基;以及
其中X或Y中至少一个不是H。
2.如权利要求1所述的化合物,其中X与Y彼此独立地选自H、Br或Cl;并且X或Y中至少一个不是H。
3.如权利要求2所述的化合物,其中X为Br或Cl;Y为H。
4.如权利要求1-3中任一项所述的化合物,其中X为Br。
5.通式I或通式II的化合物
其中
X与Y彼此独立地选自H、F、Cl、Br、I和苄基;以及
PG1选自甲基、甲氧基甲基、苄氧基甲基、甲氧基乙氧基甲基、苄基、4-甲氧基苄基、2,6-二氯苄基、3,4-二氯苄基;-CH2COOH、-CH2COORx和-CH2CH2OPG2;以及
PG2为THP、SiR1R2R3或-CH2ORx;以及
R1、R2和R3彼此独立地选自甲基、异丙基、叔丁基和苯基;
Ra为氢、羟基-ORx、-OCOORx、-OSO2Rx、Cl、Br、F、I、-SRx或-SO2Rx;
Rx为C1-4烷基或芳基;以及
其中X或Y中至少一个不是H。
6.用于制备通式(II)化合物的方法,其包括下列步骤:
其中
X、Y、Ra、PG1和PG2如权利要求1中所定义的。
7.如权利要求6所述的方法,其中PG2为TBDMS。
8.如权利要求6或7所述的方法,其中Ra为羟基。
9.如权利要求6所述的方法,其中
X为Br,以及
Y为氢,以及
PG1为苄基,以及
PG2为TBDMS;以及
Ra为羟基。
10.用于制备通式IV化合物的方法,其包括下列步骤:
a)氢化和还原通式II的化合物以获得通式III的外消旋化合物;
b)在溶剂的存在下,使通式III的外消旋化合物与脂肪酶AK接触;以及
c)获得光学纯的化合物IV;
其中
PG2为THP或TBDMS。
11.如权利要求10所述的方法,其中所述溶剂选自乙酸乙烯酯、己烷、庚烷和氯仿。
12.如权利要求10或11所述的方法,其中在约8-12的pH值,优选地在约9-10的pH值进行氢化。
13.制备曲前列环素(18)的方法,其包括下列步骤:
14.新的中间体化合物,其选自:
通过下列的实施例进一步地例示本发明,且不以任何方式将本发明限制于实施例。
实施例
(1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-六氢化-2-羟基-1-[(3S)-3-羟基辛基]-1H-苯并[f]茚-5-基]氧基]乙酸(曲前列环素,18)的制备
实施例1:溴苯甲醛2的制备
如Bioorganic & Medicinal Chemistry Letters,20(3),1169-1172;2010或根据Journal of Organic Chemistry 67(26),9248-9256;2002中所述制备化合物2。
实施例2:烯丙基醚3的制备
向配备冷凝器、温度端口和搅拌器的干燥的5L三颈圆底烧瓶中添加含6-溴-间羟基苯甲醛(2,250g,1.23摩尔)的二甲基甲酰胺(1250mL)。在搅拌下向由此得到的溶液中添加无水碳酸钾(538g,3.81摩尔)。向这一混合物中缓慢地添加烯丙基溴并且在搅拌下维持反应混合物直到反应完成(通过以己烷:二氯甲烷:乙酸乙酯:7:4:0.5的薄层色谱法(TLC)监控)。反应完成后添加二氯甲烷和水并且搅拌由此得到的溶液,以及进行层分离。用10%NaOH处理有机层并且重复层分离。在减压下蒸馏出所获得的有机层,获得为褐色液体物质的6-溴-3-烯丙氧基苯甲醛;产量290g(98%),HPLC纯度>95%。
1HNMR(CDCl3):4.55-4.65(s,2H),5.15-5.40(m,2H),6.00-6.10(m,1H),7.0-7.10(dd,1H),7.18-7.24(d,1H),7.52-7.56(d,1H),10.1(s,1H,CHO)。
实施例3:克莱森重排为烯丙基-苯甲醛4a和4b(WO0176693)
向50L玻璃烧瓶组件中添加含烯丙基醚(3,600g,2.48摩尔)的邻二氯苯(18L)。在油浴中缓慢加热由此得到的溶液直到155℃并且停留在这一温度40小时。冷却反应物料并且用10%NaOH溶液萃取。将邻二氯苯的有机层回收到玻璃烧瓶组件并且重复加热操作两次。用HCl处理水层并且萃取到二氯甲烷。部分地蒸馏二氯甲烷层并且向烧瓶添加己烷。在冷却下溶液静置1-2天然后使用布氏漏斗过滤,用冷的己烷洗涤滤饼,产生为深褐色至带黑色粉末的6-溴-3-羟基-2-烯丙基苯甲醛;总产量160g(27%),HPLC纯度>93%。
实施例4:苄醚5的制备
向配备回流冷凝器、温度端口和搅拌器的干燥的5L四颈圆底烧瓶中添加含间羟基苯甲醛(4a,100g,0.41摩尔)的甲醇。向由此得到的溶液添加氯化苄(175mL,1.26摩尔)。然后缓慢地加热这一混合物至回流并且在搅拌下保持3-4小时,直到反应完成(通过TLC监控,己烷:二氯甲烷:乙酸乙酯:7:4:0.5)。反应完成后,添加水和二氯甲烷。化合物萃取到有机层后,用10%NaOH溶液洗涤有机层,然后在减压下蒸馏出二氯甲烷。向油状物质添加己烷并且温度设定在0-10℃。搅拌203小时后,在布氏漏斗中过滤由此得到的浆体,用己烷洗涤滤饼,产生为白色至类白色粉末的6-溴-3-苄氧基-2-烯丙基苯甲醛;产量110g(80%);HPLC纯度>99%。
实施例5:氯代醇7的制备
实施例6:叔丁基二甲基硅烷醚8的制备
实施例7:三甲基硅烷基炔烃9的制备
实施例8:炔烃10的制备
实施例9:炔基醇11的制备
在氮气下向10(20.3g;75.6mmol)的90ml干燥THF溶液中经由加料漏斗在10分钟内逐滴添加含1.3M异丙基氯化镁氯化锂络合物的THF(58.1mL,75.6mmol)。在室温下(RT)搅拌棕色溶液15分钟。向这一溶液中添加5(12.5g;37.8mmol)的120mL干燥THF溶液。在RT下搅拌由此得到的溶液1小时。TLC(10%乙酸乙酯:己烷-UV检测)指示起始物质的消耗。用氯化铵水溶液(200mL)淬灭反应溶液并且用500mL叔丁基甲基醚(MTBE)稀释。分离层。用MTBE(2×500mL)萃取水层。合并有机层并且用无水硫酸钠干燥。通过烧结玻璃漏斗过滤溶剂。在真空中浓缩滤液,产生24.1g油状粗产物。在330g Agela硅胶柱上,使用Isco自动化色谱分析系统纯化粗产物,用0-10%乙酸乙酯:己烷洗脱,回收16g(71%)的所需产物11,并回收3.7g(18%)的10。(NMR,MS)
实施例10:分子内非立体选择性Pauson-Khand环化(PKC)为环戊烯酮12
在带有磁力搅拌棒、回流冷凝器、三通旋塞阀真空入口接头和外部温度控制的1L圆底烧瓶中,在RT下将11(16.0g;26.7mmol)溶解于271mL二噁烷中。将系统置于真空下10秒随后充斥一氧化碳。这一程序再重复两次。在系统处于充斥一氧化碳时,添加羰基钴(3.6g,10.5mmol)。再排空系统并且用一氧化碳充满。搅拌混合物同时将白光源指向反应瓶,维持35-40℃反应温度。48小时后,TLC(10%乙酸乙酯:己烷UV检测)指示起始物质的消耗。在真空下浓缩滤液以产生18.1g油状粗产物。在二氧化硅上,使用SiliaFlash G 60二氧化硅纯化粗产物,用5-60%乙酸乙酯:己烷洗脱以回收9.2g(55%)的所需产物12。(NMR,MS)
实施例11:同时还原裂解溴、羟基和苄醚部分,并且还原为环戊酮13
程序A:在氮气中搅拌下,在带有磁力搅拌器的2L圆底烧瓶中将12(10.0g;15.9mmol)溶解于802mL甲醇。在氮气下添加碳酸氢钾(4.7g;47.8mmol,3.0eq.)。使氮气鼓泡通过溶液30分钟以使混合物脱气。在这时,在氮气下添加10%钯碳(4.5g)。再继续脱气15分钟。然后用氢气使反应混合物饱和20分钟。然后使用6个含有氢气的气球将反应系统置于氢气下。搅拌反应过夜。TLC(30%乙酸乙酯:己烷,UV和钼酸铈(IV)铵染色)表明剩余起始物质。用氢气再充气气球并且再搅拌混合物一天。总计48小时后,TLC指示没有剩余起始物质。向反应混合物添加碳酸氢钾(3.1g,2.0eq.)并且搅拌10小时(pH=10)。当使氮气通过漏斗时,通过Whatman优质滤纸过滤反应混合物,并随后通过短的硅藻土柱(Celite plug)再过滤以除去任何残留的催化剂。然后用150mL乙酸乙酯冲洗柱。在真空中浓缩滤液以产生14.0g残留物。将残留物溶于200mL乙酸乙酯中并且再通过硅藻土过滤。用150mL乙酸乙酯冲洗硅藻土柱。在真空中浓缩滤液以产生7.1g粘性油状粗产物。粗产物溶解于10mL己烷中并且上样至120g Agela硅胶柱,使用Isco自动化色谱分析系统纯化粗产物,用0-30%乙酸乙酯:己烷洗脱以回收4.0g(57%)的所需产物13(NMR,MS)。
程序B:在氮气中搅拌下,在带有磁力搅拌器的3L圆底烧瓶中将12(21.5g;34.2mmol)溶解于1.7L甲醇中。在氮气下添加碳酸氢钾(10.2g;102.7mmol,3.0eq.)。使氮气鼓泡通过反应混合物30分钟以使混合物脱气。30分钟脱气后,在氮气下添加10%钯碳(9.6g)。再继续脱气15分钟。在这时,用氢气在反应混合物中鼓泡20分钟。6个气球连接在反应烧瓶上并且在氢气下搅拌系统过夜。TLC(30%乙酸乙酯:己烷,UV和钼酸铈(IV)铵染色)表明剩余起始物质。用氢气再充气气球并且再搅拌混合物一天。48小时后,TLC指示仍剩余一些起始物质。用氢气再充气气球并且在搅拌混合物一天。72小时后,TLC指示没有剩余起始物质。向反应混合物添加碳酸氢钾(6.8g;67.9mmol,2eq.)并且搅拌反应混合物10分钟。当充斥氮气时,通过Whatman滤纸过滤反应混合物,随后通过硅藻土柱以除去任何残余的催化剂。将滤液就此用于下一步骤。
实施例12:立体选择性硼氢化钠还原为环戊醇(14)
程序A(使用来自氢化反应的纯化的化合物):在RT和氮气中搅拌下,在260mL甲醇中用1.4mL 10%NaOH处理一部分13(3.0g;6.7mmol)。90分钟后,TLC(20%乙酸乙酯:己烷,UV和钼酸铈(IV)铵染色)指示底部斑点消失。将反应混合物冷却至-10℃并且添加硼氢化钠(255mg;6.7mmol)。1小时后,TLC(30%乙酸乙酯:己烷)指示仍剩余起始物质。再添加255mg(6.7mmol)硼氢化钠。2小时后,在-10℃下,TLC指示没有剩余起始物质。使反应回温至RT并且搅拌过夜。用乙酸酸化反应混合物至pH 6。用100mL水稀释反应并且在真空中浓缩。用乙酸乙酯(300mL)稀释残留物,用25mL 5%碳酸氢钠(1×100mL)和盐水(1×100mL)洗涤。通过无水硫酸钠干燥有机层并且通过烧结玻璃漏斗过滤。在真空中浓缩滤液以回收3.0g粗产物。将粗产物溶解于15mL己烷中并且上样至40g Agela硅胶柱上。将柱置于自动化Isco色谱分析系统上。通过0-15%乙酸乙酯:己烷20分钟、15-20%乙酸乙酯:己烷5分钟、20-25%乙酸乙酯:己烷5分钟并且最终25-40%乙酸乙酯洗脱粗产物,回收1.7g(57%)的所需产物14。
程序B(使用来自氢化反应的反应滤液):在RT和氮气中搅拌下,在5L圆底烧瓶中用160mL 10%NaOH处理3000mL(73.5mmol)的13反应滤液。2小时后,TLC(20%乙酸乙酯:己烷,UV和钼酸铈(IV)铵染色)指示底部差向异构体(斑点)消失。将反应混合物冷却至-10℃。一次添加硼氢化钠(3.1g;84.2mmol)。1小时后,TLC(30%乙酸乙酯:己烷)指示仍剩余起始物质。再添加3.1g(84.2mmol)硼氢化钠。总计2小时后,在-10℃下,TLC指示没有剩余起始物质。使反应回温至RT并且搅拌过夜。用乙酸酸化反应混合物至pH 6。用200mL水稀释反应并且在真空中浓缩。用乙酸乙酯(1600mL)稀释残留物,用25mL 5%碳酸氢钠(1×500mL)和盐水(1×300mL)洗涤。通过无水硫酸钠干燥有机层并且通过烧结玻璃漏斗过滤。在真空中浓缩滤液以回收38.4g粗产物。将粗产物溶解于65mL己烷中并且上样至770g SilicaFlashG60柱上,用5%乙酸乙酯:己烷(1×1000mL)、10%乙酸乙酯:己烷(1×1000mL)、15%乙酸乙酯:己烷(1×1000mL)、20%乙酸乙酯:己烷(1×1000mL)、25%乙酸乙酯:己烷(1×1000mL)、30%乙酸乙酯:己烷(1×1000mL)、35%乙酸乙酯:己烷(1×1000mL)、和40%乙酸乙酯:己烷(1×500mL)洗脱以获得16.7g(44%产率)的所需产物14。
实施例13:苯酚(15)的烃化作用
在氩气下向14(0.5g;1.11mmol)的丙酮(45mL)溶液中添加碳酸钾(1.5g;11.1mmol,10eq,),同时氩气流通过混合物5分钟。添加氯乙腈(1.4mL;22.3mmol,20eq.)并且将混合物加热至回流5小时。TLC(25%乙酸乙酯:己烷)指示反应完成。冷却反应混合物至RT并且通过硅藻土柱过滤。在真空中浓缩滤液以产生1.8g油状粗产物。将油储存在0℃下过夜。将粗产物溶解于10mL的20%乙酸乙酯:己烷并且通过Siliaflash硅胶,用20%乙酸乙酯:己烷(2×100mL)洗脱。在真空中浓缩溶剂以回收0.48g油。然后用50%乙酸乙酯:己烷(3×100mL)冲洗二氧化硅柱,TLC指示理想的产物以两部分存在。合并两部分并纯化。将粗产物溶解于8mL己烷中并且上样至12g Agela硅胶柱上。用0-30%乙酸乙酯:己烷洗脱粗产物20分钟以回收0.35g(65%)所需产物15a。
实施例14:用脂肪酶AK酶促拆分成非对映体纯的乙酸盐(16a)
在RT下将一部分15(18.6g;38.2mmol)溶解于400mL干燥己烷中。一次加入乙酸乙烯酯(50mL)和脂肪酶AK“AMANO”(36g)。在氮气下搅拌混合物48小时。TLC(20%乙酸乙酯:己烷)指示两个斑点都以相等的UV强度存在。这通过1H-NMR确认。通过烧结玻璃漏斗过滤反应混合物并且用250mL 1:1己烷:乙酸乙酯冲洗。在真空中浓缩滤液以回收大约21g油状物。将粗产物溶解于50mL己烷中并且上样至330g Agela硅胶柱上。将柱置于自动化色谱分析系统上。用10-20%乙酸乙酯:己烷洗脱粗产物20分钟以回收8.7g(43%)的所需异构体16a及8.6g(43%)拆分的醇16b。
实施例15:苯氧基-乙酸(17)的制备
将一部分16a(15.8g;29.9mmol)溶解于748mL MeOH中。在5分钟内分批添加35%aq.KOH(262mL)。加热反应至回流。1小时后,TLC(30%乙酸乙酯:己烷)指示没有剩余起始物质。4小时后,TLC(100%乙酸乙酯)指示超过起点的重UV活性点。冷却反应混合物至RT,然后将其置于冰浴。添加2M HCl(600mL)以酸化反应至pH 5。用1.6L乙酸乙酯稀释反应混合物并且用饱和的NaCl水溶液(1.6L)洗涤。通过无水硫酸钠干燥有机层。通过烧结玻璃漏斗过滤溶剂。在真空中浓缩滤液以回收15.1g粘性油17,其用于下一步骤。
实施例16:曲前列环素(18)的制备
将一部分17(15.1g;29.9mmol)溶解于300mL乙腈。冷却溶液至0℃。小心地分批添加73mL 48%HF。5分钟后,TLC(100%乙酸乙酯)指示没有剩余起始物质。将反应在-20℃下储存过夜。使反应回温至RT,并剧烈搅拌下用1.5L蒸馏水稀释。形成沉淀物,继续搅拌5分钟。使固体沉降并且通过布氏漏斗过滤。用250mL蒸馏水冲洗固体。在真空下干燥固体30分钟。固体置于RT下高真空下5小时。回收17.6g固体。在300mL的己烷中搅拌物质5小时。通过布氏漏斗过滤固体并且在真空下干燥15分钟。最终将物质置于冻干器上48小时以除去任何微量的溶剂。回收10.5g(91%)所需产物曲前列环素(18)。
对本领域的那些技术人员显而易见的是,可以对本发明的方法和新的中间体做各种修改和变化。因此,意图本发明覆盖此类修改和变化,只要它们落在附加的权利要求及其等同的范围内。
Claims (2)
1.通式I或通式II的化合物:
其中
X为Br且Y为H;以及
PG1选自甲基、甲氧基甲基、苄氧基甲基、甲氧基乙氧基甲基、苄基、4-甲氧基苄基、2,6-二氯苄基、3,4-二氯苄基;-CH2COOH、-CH2COORx和-CH2CH2OPG2;以及
PG2为TBDMS;以及
Ra为羟基;以及
Rx为C1-4烷基或芳基。
2.新的中间体化合物,其选自:
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EP2943479B1 (en) | 2013-01-11 | 2020-04-15 | Corsair Pharma, Inc. | Prodrugs of treprostinil |
US9505737B2 (en) | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
JP6491203B2 (ja) | 2013-10-25 | 2019-03-27 | インスメッド インコーポレイテッド | プロスタサイクリン化合物、組成物およびその使用方法 |
CN104892555B (zh) * | 2014-03-04 | 2019-03-08 | 江苏豪森药业集团有限公司 | 曲前列尼尔中间体的制备方法 |
HU231186B1 (hu) * | 2014-10-08 | 2021-06-28 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Új eljárás treprostinil és sói előállítására |
WO2016081658A1 (en) | 2014-11-18 | 2016-05-26 | Insmed Incorporated | Methods of manufacturing treprostinil and treprostinil derivative prodrugs |
TWI540121B (zh) | 2014-12-01 | 2016-07-01 | 臺灣永光化學工業股份有限公司 | 曲前列環素二乙醇胺之合成方法及新穎中間體 |
US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
US9394227B1 (en) | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
KR101830693B1 (ko) * | 2016-04-28 | 2018-02-21 | 연성정밀화학(주) | 트레프로스티닐의 제조방법 및 이를 위한 중간체 |
EP3515430A1 (en) | 2016-09-26 | 2019-07-31 | United Therapeutics Corporation | Treprostinil prodrugs |
EP3498283A1 (en) | 2017-12-14 | 2019-06-19 | Ipsol AG | Glycosidic derivatives of treprostinil |
CN108875295A (zh) * | 2018-06-21 | 2018-11-23 | 华北电力科学研究院有限责任公司 | 一种利用析因实验设计指导有机物分子修饰改性的方法 |
JP7455144B2 (ja) | 2019-04-29 | 2024-03-25 | インスメッド インコーポレイテッド | トレプロスチニルプロドラッグの乾燥粉末組成物およびその使用方法 |
AU2020337342A1 (en) | 2019-08-23 | 2022-02-24 | United Therapeutics Corporation | Treprostinil prodrugs |
CN115916212A (zh) | 2020-04-17 | 2023-04-04 | 联合治疗公司 | 曲前列尼尔用于治疗间质性肺病 |
CN116113415A (zh) | 2020-06-09 | 2023-05-12 | 联合治疗公司 | 曲前列尼尔的富马酰基二酮哌啶前药 |
WO2022132655A1 (en) | 2020-12-14 | 2022-06-23 | United Therapeutics Corporation | Methods of treating disease with treprostinil prodrugs |
EP4301372A1 (en) | 2021-03-03 | 2024-01-10 | 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 |
US20240287105A1 (en) | 2023-01-19 | 2024-08-29 | United Therapeutics Corporation | Treprostinil analogs and related methods of making and using |
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US6242842B1 (en) | 1996-12-16 | 2001-06-05 | Siemens Matsushita Components Gmbh & Co. Kg | Electrical component, in particular saw component operating with surface acoustic waves, and a method for its production |
US6441245B1 (en) * | 1997-10-24 | 2002-08-27 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
US6242482B1 (en) * | 2000-06-05 | 2001-06-05 | United Therapeutics Corporation | Prostaglandin compounds and derivatives thereof, compositions containing the same and method of using the same for the treatment of congestive heart failure |
US6700025B2 (en) * | 2001-01-05 | 2004-03-02 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
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CA2710726C (en) * | 2010-07-22 | 2016-02-23 | Alphora Research Inc. | Synthesis of treprostinil and intermediates useful therein |
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