CN118027091A - Preparation method of treprostinil and intermediate thereof - Google Patents
Preparation method of treprostinil and intermediate thereof Download PDFInfo
- Publication number
- CN118027091A CN118027091A CN202410171330.0A CN202410171330A CN118027091A CN 118027091 A CN118027091 A CN 118027091A CN 202410171330 A CN202410171330 A CN 202410171330A CN 118027091 A CN118027091 A CN 118027091A
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- Prior art keywords
- compound
- formula
- reaction
- solvent
- allyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229960005032 treprostinil Drugs 0.000 title claims abstract description 12
- 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 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 238000005937 allylation reaction Methods 0.000 claims abstract description 10
- 150000003254 radicals Chemical class 0.000 claims abstract description 9
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 8
- 150000003624 transition metals Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 143
- 239000002904 solvent Substances 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 18
- -1 allyl halohydrocarbon Chemical class 0.000 claims description 18
- 239000004593 Epoxy Substances 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 15
- WLHPCEJPGLYEJZ-UHFFFAOYSA-N prop-2-enyltin Chemical compound [Sn]CC=C WLHPCEJPGLYEJZ-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- 230000009471 action Effects 0.000 claims description 10
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 9
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical group N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 125000005104 aryl silyl group Chemical group 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000004795 grignard reagents Chemical class 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 239000011630 iodine Chemical group 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 3
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 3
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- HHBZZTKMMLDNDN-UHFFFAOYSA-N 2-butan-2-yloxybutane Chemical compound CCC(C)OC(C)CC HHBZZTKMMLDNDN-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 101150003085 Pdcl gene Proteins 0.000 claims description 2
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 2
- HFEHLDPGIKPNKL-UHFFFAOYSA-N allyl iodide Chemical compound ICC=C HFEHLDPGIKPNKL-UHFFFAOYSA-N 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 2
- 125000000746 allylic group Chemical group 0.000 claims 1
- 238000006011 modification reaction Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 208000020193 Pulmonary artery hypoplasia Diseases 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- MNOILHPDHOHILI-UHFFFAOYSA-N Tetramethylthiourea Chemical compound CN(C)C(=S)N(C)C MNOILHPDHOHILI-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 102000030621 adenylate cyclase Human genes 0.000 description 3
- 108060000200 adenylate cyclase Proteins 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000003223 protective agent Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- ASHGTJPOSUFTGB-UHFFFAOYSA-N 3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1 ASHGTJPOSUFTGB-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 2
- 102000002045 Endothelin Human genes 0.000 description 2
- 108050009340 Endothelin Proteins 0.000 description 2
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000006647 Pauson-Khand annulation reaction Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000002308 endothelin receptor antagonist Substances 0.000 description 2
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 2
- 229960001123 epoprostenol Drugs 0.000 description 2
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
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- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
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- 238000006467 substitution reaction Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical group CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 2
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- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
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- 101000605431 Mus musculus Phospholipid phosphatase 1 Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010039163 Right ventricular failure Diseases 0.000 description 1
- 208000000924 Right ventricular hypertrophy Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- TVJORGWKNPGCDW-UHFFFAOYSA-N aminoboron Chemical compound N[B] TVJORGWKNPGCDW-UHFFFAOYSA-N 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WNTGVOIBBXFMLR-UHFFFAOYSA-N bicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1C2 WNTGVOIBBXFMLR-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
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- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- FEQPHYCEZKWPNE-UHFFFAOYSA-K trichlororhodium;triphenylphosphane Chemical compound Cl[Rh](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FEQPHYCEZKWPNE-UHFFFAOYSA-K 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of treprostinil and an intermediate thereof, belonging to the field of pharmaceutical chemistry. Intermediate 3-alkoxy-2-allylbenzaldehyde
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of treprostinil and an intermediate thereof.
Background
Pulmonary arterial hypertension (Pulmonary arterial hypertension, PAH) is a group of diseases caused by a variety of pathogenic factors, which ultimately lead to sustained increases in pulmonary vascular resistance, clinically manifested as tired dyspnea, reduced motor endurance, and ultimately developed as right ventricular hypertrophy, right heart failure. Current diagnostic criteria for PAH are: in the resting state at sea level, mean pulmonary arterial hypertension (mean pulmonary arterialpressure, mPAP) > 25mmHg and pulmonary capillary wedge pressure < 15mmHg were measured by the right heart catheterization method.
The mortality rate and disability rate of PAH patients are extremely high, no specific treatment scheme exists so far, and drug treatment is still a main treatment means. For example, different PAH therapeutic targets corresponding to PAH pathogenesis: prostacyclin and its analogs, endothelin Receptor Antagonists (ERA), phosphodiesterase-5 (Phosphodiesterases, pde 5) inhibitors and calcium antagonists (Caleium Channel Bloeker, CCB), respectively, are directed against the adenylate cyclase (ADENYLATE CYCLASE, AC), endothelin (ET), nitric Oxide (NO), and calcium channel pathways. Wherein, the prostacyclin can activate adenylate cyclase in vivo, promote generation of cyclic adenosine monophosphate (Cyclic adenosine monophosphate, cAMP) and play a role in dilating blood vessels.
For the synthetic method of treprostinil, CN1283184a discloses the following preparation method:
The synthetic strategy is to take m-methoxyphenol as a raw material, construct a skeleton structure of treprostinil through claisen rearrangement, oxidization, nucleophilic addition of a side chain, asymmetric reduction, pauson-Khand cyclization reaction, and then synthesize treprostinil through the steps of hydrogenation reduction, chiral control group removal, sodium borohydride reduction, deprotection and the like. The preparation method of the key intermediate 3-alkoxy-2-allyl benzaldehyde in the strategy is complex, low in yield and poor in reproducibility, and the development of industrial scale-up production is greatly limited by using dangerous reagents such as butyl lithium.
At present, the literature reports on the preparation of 3-alkoxy-2-allylbenzaldehyde include, in addition to the above-mentioned methods, examples of alkylation using bromobenzaldehyde acetal compounds as reported by org. However, in the application of the reagent, the condition is harsh, the technology is complex, the dimethoxy acetalation substrate is unstable, and degradation is easy to occur in the storage and reaction processes.
Therefore, a simple and efficient synthesis method is developed aiming at the key intermediate 3-alkoxy-2-allyl benzaldehyde, the reaction route is shortened, and the improvement of the yield is a key point for solving industrialization.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a preparation method of treprostinil and a key intermediate 3-alkoxy-2-allylbenzaldehyde, which shortens the synthetic route, has mild reaction conditions and simple and convenient operation, improves the reaction yield, and is suitable for industrial production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in one aspect, the present invention provides a process for the preparation of a compound of formula (4), comprising the steps of:
S1: subjecting a compound of the following formula (2) to allylation reaction, free radical allylation reaction or transition metal catalyzed coupling reaction to obtain a compound of the formula (3);
s2: hydrolyzing a compound of the following formula (3) to obtain a compound of the formula (4);
The reaction formula is as follows:
Wherein R 1 represents alkyl, alkoxy, alkylene oxide, alkoxyalkyl, alkylsilyl, arylsilyl, and, Any one of them; n and m independently represent an integer from 1 to 6, e.g. n and m independently are 1,2,3,4,5 or 6; r 2 independently represents an alkyl group or an aryl group.
Preferably, the alkyl group is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms; the alkoxy is straight-chain or branched-chain alkoxy with 1-6 carbon atoms; the epoxy alkyl is epoxy alkyl with 3-10 carbon atoms; the alkoxyalkyl group is an alkoxyalkyl group having 1 to 6 carbon atoms and 1 to 3 oxygen atoms; the aryl is a monocyclic or condensed ring aryl with 6-10 carbon atoms.
Further preferably, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the alkoxy is methoxy, ethoxy or propoxy; the epoxy alkyl is epoxy propyl, epoxy butyl, epoxy amyl or epoxy hexyl; the alkoxyalkyl group is The aryl is phenyl.
Still more preferably, R 1 represents methyl, ethyl, Any one of the following.
X represents halogen, such as fluorine, chlorine, bromine, iodine; x is preferably bromine.
Pg representsR 3 independently represents alkyl, n 1 represents an integer from 1 to 6, for example n 1 is 1,2,3,4,5 or 6.
Preferably, R 3 independently represents a straight or branched alkyl group having 1 to 6 carbon atoms, and n 1 represents an integer of 2 to 4.
Further preferably, R 3 independently represents methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl; n 1 is 2 or 3.
In one embodiment of the invention, step S1 synthesizes compound (3) using method 1:
Method 1: converting the compound of the formula (2) into a corresponding Grignard reagent in an aprotic solvent at a low temperature under the action of a metal reagent, and then reacting with allyl halohydrocarbon to obtain a compound of the formula (3);
further, the metal reagent is any one of methyl magnesium bromide, methyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride compound, n-butyl lithium, isobutyl lithium and tert-butyl lithium; n-butyllithium is preferred;
Further, the low temperature is-80-0 ℃;
Further, the aprotic solvent comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, 2-butyl ether, 1, 4-dioxane and toluene; tetrahydrofuran is preferred;
Further, the allyl halohydrocarbon is X is fluorine, chlorine, bromine or iodine; further preferably, the allyl halogenated hydrocarbon is allyl chloride, allyl bromide, allyl iodide; more preferably allyl bromide;
Further, the molar ratio of the compound of formula (2) to the metal reagent to the allylic halohydrocarbon is 1:1-1.5:1-1.5.
In another embodiment of the present invention, step S1 synthesizes compound (3) using method 2:
the compound of the formula (2) and trialkyl allyl tin are reacted under the action of a free radical initiator, and the compound of the formula (3) is obtained under the conditions of solvent and heating;
further, the free radical initiator is Azobisisobutyronitrile (AIBN);
Further, the trialkyl allyltin reagent includes, but is not limited to, any one of trimethylallyltin, triethylallyltin, tri-n-butylallyltin; preferably tri-n-butyl allyl tin;
further, the solvent is an alkane solvent, a benzene solvent or an ether solvent; preferably, the alkane solvent is cyclohexane; the benzene solvent is toluene; the ether solvent is tetrahydrofuran;
further, the reaction temperature is 30-100 ℃; preferably 60-80 ℃;
further, the molar ratio of the azodiisobutyronitrile to the compound of formula (2) is 0.2-0.5:1.0;
further, the molar ratio of the trialkyl allyl tin to the compound of formula (2) is 1.0 to 2.0:1.0.
In yet another embodiment of the present invention, step S1 synthesizes compound (3) using method 3:
Reacting the compound of formula (2) with a transition metal catalyst and a ligand, and reacting with a trialkyl allyl tin reagent under the conditions of no oxygen, solvent and heating to generate a compound of formula (3);
Further, the transition metal catalyst is a palladium catalyst including, but not limited to, tetrakis (triphenylphosphine) palladium, pdCl 2(PPh3)2、PdCl2(MeCN)2、Pd2(dba)3, etc.; tetrakis (triphenylphosphine) palladium is preferred;
Further, the ligand is an organic phosphine ligand, preferably triphenylphosphine;
Further, the solvent is benzene solvent, ether solvent or amide solvent; the benzene solvent is preferably toluene; the ether solvent is preferably 1, 4-dioxane; the amide solvent is preferably N, N-Dimethylformamide (DMF);
Further, the reaction temperature is 30-150 ℃, preferably 80-120 ℃;
Further, the trialkyl allyltin reagent includes, but is not limited to, any one of trimethylallyltin, triethylallyltin, tri-n-butylallyltin; preferably tri-n-butyl allyl tin;
Further, the molar ratio of the transition metal catalyst to the compound of formula (2) is 0.05-0.2:1; the molar ratio of the trialkyl allyl tin to the compound of formula (2) is 1.0-2.0:1.0.
In one embodiment of the present invention, the compound of formula (3) is hydrolyzed in step S2 under acid and solvent conditions to provide the compound of formula (4);
Further, the acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like; p-toluene sulfonic acid is preferred;
Further, the solvent is water, acetone, acetic acid, tetrahydrofuran, 1,4 dioxane or a solvent obtained by mixing the solvents according to any proportion; preferably a water-tetrahydrofuran mixed solvent;
Further, the molar ratio of the acid to the compound of formula (3) is 0.05 to 0.2:1.0.
In another aspect, the present invention provides a method for preparing treprostinil as a compound of formula (1), comprising the steps of:
S1: subjecting a compound of the following formula (2) to allylation reaction, free radical allylation reaction or transition metal catalyzed coupling reaction to obtain a compound of the formula (3);
s2: hydrolyzing a compound of the following formula (3) to obtain a compound of the formula (4);
s3: reacting a compound of the following formula (5) with a compound of the formula (4) under the action of a metal reagent to obtain a compound of the formula (6);
s4: carrying out hydroxyl oxidation on a compound of the following formula (6) to obtain a compound of the formula (7);
s5: carrying out asymmetric reduction on a compound of the following formula (7) to obtain a compound of the formula (8);
S6: hydroxy protecting the compound of the following formula (8) to obtain a compound of the formula (9);
S7: a compound of the following formula (9) is subjected to ring closure reaction under the atmosphere of a transition metal catalyst and carbon monoxide to obtain a compound of the following formula (10);
S8: carrying out catalytic hydrogenation on a compound of the following formula (10) to obtain a compound of the following formula (11);
S9: carbonyl reduction is carried out on the compound of the following formula (11) to obtain a compound of the following formula (12);
S10: removing a protecting group from a compound of the following formula (12) to obtain a compound of the following formula (13);
S11: the compound of the following formula (13) is subjected to acetic acid group substitution to obtain the compound of the formula (1), namely treprostinil.
The reaction formula is as follows:
wherein R 1 and Pg are as defined above.
Pg 2 and Pg 3 independently represent alkyl, alkoxy, alkylene oxide, alkoxyalkyl, alkylsilyl, arylsilyl, and,Any one of them; n and m independently represent an integer from 1 to 6, e.g. n and m independently are 1,2,3,4,5 or 6; r 2 independently represents an alkyl group or an aryl group.
Preferably, the alkyl group is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms; the alkoxy is straight-chain or branched-chain alkoxy with 1-6 carbon atoms; the epoxy alkyl is epoxy alkyl with 3-10 carbon atoms; the alkoxyalkyl group is an alkoxyalkyl group having 1 to 6 carbon atoms and 1 to 3 oxygen atoms; the aryl is a monocyclic or condensed ring aryl with 6-10 carbon atoms.
Further preferably, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the alkoxy is methoxy, ethoxy or propoxy; the epoxy alkyl is epoxy propyl, epoxy butyl, epoxy amyl or epoxy hexyl; the alkoxyalkyl group is The aryl is phenyl.
Still more preferably, pg 2 and Pg 3 independently represent methyl, ethyl, Any one of them; preference/>
In one embodiment of the present invention, the compound of formula (5) is deprotonated in step S3 under the action of a metal reagent, and then undergoes an addition reaction with the compound of formula (4) under anhydrous and anaerobic conditions to obtain the compound of formula (6);
Further, the metal reagent is n-butyllithium, isobutyllithium, tert-butyllithium, methylmagnesium bromide, methylmagnesium chloride, isopropylmagnesium bromide or isopropylmagnesium chloride and complexes thereof; n-butyllithium is preferred;
further, the reaction solvent is an ether solvent, preferably tetrahydrofuran;
Further, the reaction temperature of deprotonation is-80-0 ℃, preferably-80-60 ℃;
further, the addition reaction temperature is 20-40 ℃, preferably 20-30 ℃;
Further, the molar ratio of the compound of formula (4) to the compound of formula (5) is 1:1-1.5;
further, the molar ratio of the compound of formula (5) to the metal reagent is 1:1 to 1.5.
In one embodiment of the present invention, the hydroxyl group in the compound of formula (6) in step S4 undergoes an oxidation reaction to give the compound of formula (7);
further, the oxidation conditions are methods known in the art, including but not limited to PCC, PDC oxidation, DMSO-mediated oxidation, IBX or Dess-Martin oxidation; preferably IBX or Dess-Martin oxidation;
further, the molar ratio of the compound of formula (6) to the oxidizing agent is 1:1-2.
In one embodiment of the invention, the compound of formula (7) in step S5 is subjected to asymmetric carbonyl reduction in the presence of a chiral reducing reagent to give a compound of formula (8);
further, the chiral reducing reagent is: (-) -diisopinosylchloroborane, (R or S) -CBS-Me/borane, or (R) -B-isoppinosyl-9-borane bicyclo [3.3.1] nonane; preferably (R) -CBS-Me/borane combinations;
Further, the reaction temperature is-80 to 0 ℃, preferably-30 to-10 ℃;
further, the molar ratio of the compound of formula (7) to the chiral reducing reagent is 1-2:1.
In one embodiment of the present invention, the compound of formula (8) in step S6 is subjected to a hydroxy protection reaction under the action of a base and a hydroxy protecting agent to give a compound of formula (9);
Further, the hydroxyl protecting agent is dimethyl tertiary butyl chlorosilane (TBDMSCl) or tertiary butyl disilyl triflate (TBDMSOTf), preferably tertiary butyl disilyl triflate;
Further, the base is an organic base, including triethylamine, diisopropylethylamine, pyridine, 2, 6-lutidine, 4-N, N-dimethylaminopyridine; preferably 2, 6-lutidine;
further, the reaction temperature is 0-40 ℃, preferably 20-30 ℃;
further, the molar ratio of the compound of formula (8), the base and the hydroxyl protecting agent is 1:1-5:1-2.
In one embodiment of the invention, in the step S7, the compound of the formula (9) is subjected to Pauson-Khand reaction under the action of a metal catalyst, carbon monoxide atmosphere and an additive to obtain a compound of the formula (10);
further, the catalyst is selected from Co 2(CO)8、Mo2(CO)6、[RhCl(CO)2]2 or Mo (Co) 3(DMF)3; co 2(CO)8 is preferred;
Further, the additive is an amine N-oxide, such as morpholine N-oxide (NMO), trimethylamine N-oxide (TMNO) or tetramethylthiourea (TMTU); tetramethyl thiourea is preferred;
further, the reaction temperature is 20-110 ℃, preferably 60-90 ℃;
Further, the molar ratio of the compound of formula (9) to the catalyst and the additive is 1:0.1-0.5:0.2-1.0.
In one embodiment of the present invention, the compound of formula (10) is hydrogenated in step S8 under a catalyst and a pressure to obtain the compound of formula (11);
Further, the catalyst is palladium carbon, palladium hydroxide, platinum dioxide, rhodium chloride (triphenylphosphine) and the like; palladium on charcoal is preferred;
Further, the reaction temperature is 0-80 ℃, preferably 20-50 ℃;
further, the reaction pressure is 1 to 10bar, preferably 5 to 10bar.
In one embodiment of the present invention, in step S9, the compound of formula (11) is carbonyl reduced with a reducing agent to provide a compound of formula (12);
Further, the reducing agent is sodium borohydride, potassium borohydride, lithium aluminum hydride, lithium triethylborohydride, diisobutylaluminum hydride, lithium triethylaluminum hydride, lithium tri-tert-butylaluminum hydride or aminoborane; sodium borohydride is preferred;
further, the reaction temperature is-80 to 10 ℃, preferably-10 to 0 ℃.
In one embodiment of the present invention, the compound of formula (12) is deprotected in step S10 under a fluorine-containing reagent or acidic condition to give a compound of formula (13);
Specifically, in the fluorine-containing reagent condition, the fluorine-containing reagent is selected from tetrabutylammonium fluoride, hydrofluoric acid-triethylamine complex, tetrabutylammonium fluoride-tertiary butanol complex or potassium fluoride; tetrabutylammonium fluoride is preferred;
Further, the reaction temperature is-40-120 ℃; preferably 0 to 30 ℃;
specifically, under acidic conditions, the acid is an inorganic acid or an organic acid, and the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; preferably sulfuric acid; the organic acid is selected from trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid or boron trifluoride diethyl ether; p-toluene sulfonic acid is preferred;
further, the reaction temperature is 0 to 100 ℃, preferably 20 to 80 ℃.
In one embodiment of the present invention, in step S11, the compound of formula (13) is reacted with a haloacetic acid under the action of a base to give the compound of formula (1);
Further, the base is an inorganic base or an organic base including, but not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, or DBU; sodium carbonate, potassium carbonate or DBU are preferred;
further, the reaction temperature is 0 to 100 ℃, preferably 20 to 40 ℃.
Compared with the prior art, the invention has the following beneficial effects:
The preparation method shortens the synthetic route, has mild reaction conditions and is simple and convenient to operate; raw materials are cheap and easy to obtain, and waste material generation is reduced; the yield of the final product is obviously improved, and the method is suitable for industrial production.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below in connection with specific embodiments, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. In addition, the raw materials related to the invention are common commercial products unless otherwise specified.
Example 1:
S1: synthesis of Compound of formula (3)
N-butyllithium (1.6M, 89 mL) was slowly added dropwise to a solution of the compound of formula (2) (50 g,128.5 mmol) in anhydrous tetrahydrofuran (320 mL) in a nitrogen atmosphere at-78deg.C, stirring was continued until the material was consumed after the addition was completed, allyl bromide (13.5 mL) was then added dropwise, stirring was continued and slowly warmed to room temperature after the addition was completed, and TLC monitored to complete the reaction. The reaction solution was poured into saturated ammonium chloride, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried and concentrated to give a crude product (NMR purity 76%) which was used directly in the next step.
1HNMR(400MHz,CDCl3)δ7.27(dt,J＝7.6,0.9Hz,1H),7.11(t,J＝7.8Hz,1H),6.85(dd,J＝8.0,1.2Hz,1H),5.91(m,1H),5.49(s,1H),5.16(d,J＝16.7Hz,2H),4.95(s,2H),3.91(m,4H),3.60(t,J＝9.3Hz,2H),3.55(d,J＝10.2Hz,2H),1.97(m,2H),0.93(t,J＝9.3Hz,2H),0.04(s,7H).
S2: synthesis of Compound of formula (4)
The compound of formula (3) (30 g,85.7 mmol) was dissolved in a tetrahydrofuran-water mixed solvent (150/50 mL), p-toluenesulfonic acid (10 mol%) was added, and the mixture was stirred at room temperature until the reaction was complete. The reaction was quenched with saturated aqueous sodium bicarbonate, concentrated to remove tetrahydrofuran, extracted three times with ethyl acetate, and the organic phases were combined and concentrated to give the compound of formula (4) (24.5 g, 98%).
1H NMR(400MHz,CDCl3)δ9.99(s,1H),7.60(dd,J＝8.1,1.4Hz,1H),7.34–7.27(m,1H),6.96(dd,J＝7.5,1.3Hz,1H),5.83(tt,J＝11.2,10.0Hz,1H),5.18(d,J＝11.1Hz,2H),4.96(s,2H),3.633.55(m,5H),0.98–0.90(m,2H),0.05(s,8H).
S3: synthesis of Compound of formula (6)
The compound of formula (5) (8.14 g,30.3 mmol) was dissolved in 60mL of anhydrous tetrahydrofuran, and n-butyllithium (33.3 mL,33.3 mmol) was added dropwise at-80℃under argon atmosphere, followed by reaction at-80℃for 1h. A solution (10 mL) of the compound of formula (4) (8.04 g,27.55 mmol) in tetrahydrofuran was then added to the reaction solution and slowly warmed to room temperature. After TLC monitored the reaction was complete, saturated ammonium chloride solution was added dropwise at 0deg.C for quenching, extracted three times with ethyl acetate and water, washed with salt, and dried. Purification by column layer separation gave the compound of formula (6) (11.6 g, 75%).
1H NMR(400MHz,CDCl3)δ7.327.23(m,2H),6.85(dd,J＝7.6,1.5Hz,1H),5.91(tt,J＝16.6,10.2Hz,1H),5.76–5.70(m,1H),5.17–5.04(m,3H),4.95(s,1H),3.70(p,J＝6.8Hz,1H),3.64–3.50(m,4H),2.51(td,J＝8.7,2.0Hz,2H),1.841.68(m,2H),1.641.54(m,2H),1.441.31(m,4H),1.341.27(m,1H),0.970.86(m,5H),0.84(s,6H),0.05(d,J＝5.9Hz,14H).
S4: synthesis of Compound of formula (7)
The compound of formula (6) (11.6 g,20.7 mmol) was dissolved in 40mL acetonitrile solvent, iodoxybenzoic acid (IBX) (8.9 g,31.79 mmol) was added at 0deg.C and refluxed at 80deg.C. After TLC monitored the reaction was completed, the reaction was cooled to room temperature, the oxidant was removed by filtration, and the solvent was removed by spinning under reduced pressure. The compound of formula (7) was isolated and purified by column chromatography (10.6 g, 91%).
1H NMR(400MHz,CDCl3)δ7.93(dd,J＝7.8,1.7Hz,1H),7.45(t,J＝7.9Hz,1H),6.95(dd,J＝8.0,1.7Hz,1H),5.88(tt,J＝16.7,9.9Hz,1H),5.12(m,2H),4.96(s,1H),3.773.67(m,3H),3.60(td,J＝9.3,0.8Hz,2H),2.642.51(m,2H),1.75(m,2H),1.58(m,2H),1.44–1.36(m,1H),1.40–1.27(m,4H),0.93(t,J＝9.3Hz,2H),0.92–0.86(m,3H),0.84(s,6H),0.05(d,J＝5.9Hz,14H).
S5: synthesis of Compound of formula (8)
Borane tetrahydrofuran complex (31 mL,31 mmol) was dissolved in 200mL anhydrous dichloromethane, and a toluene solution (32 mL,32 mmoL) of the 1M (R) -CBS-Me/borane composition was added dropwise at-20℃under argon atmosphere, followed by stirring for about 30 minutes. A solution (80 mL) of the compound of formula (7) (11.54 g,20.68 mmol) in methylene chloride was then added dropwise to the reaction mixture and reacted at-20 ℃. After TLC monitored the end of the reaction, it was quenched with water, extracted with dichloromethane and purified by column chromatography to give the compound of formula (8) (9.63 g, 83%).
1H NMR(400MHz,CDCl3)δ7.3–7.23(m,2H),6.85(dd,J＝7.6,1.5Hz,1H),5.91(tt,J＝16.6,10.2Hz,1H),5.76–5.70(m,1H),5.175.04(m,3H),4.95(s,1H),3.70(p,J＝6.8Hz,1H),3.643.50(m,4H),2.51(td,J＝8.7,2.0Hz,2H),1.841.68(m,2H),1.641.54(m,2H),1.44–1.31(m,4H),1.34–1.27(m,1H),0.97–0.86(m,5H),0.84(s,6H),0.05(d,J＝5.9Hz,14H).
S6: synthesis of Compound of formula (9)
The compound of formula (8) (5.93 g,10.57 mmol) was dissolved in anhydrous dichloromethane, and 2, 6-lutidine (6.2 mL,52.85 mmol) and tert-butyldimethylsilyl triflate (5.97 mL,22.3 mmol) were added sequentially at 0deg.C and reacted at room temperature. After TLC detected that the reaction was completed, washing with water, extraction with methylene chloride, and separation and purification by column chromatography gave a compound of formula (9) (9.21 g, 96%).
1H NMR(400MHz,CDCl3)δ7.28–7.23(m,1H),7.19(dd,J＝8.0,7.2Hz,1H),6.85(dd,J＝7.9,1.3Hz,1H),5.95–5.83(m,1H),5.45(td,J＝2.0,0.7Hz,1H),5.175.09(m,2H),4.95(s,2H),3.70(p,J＝6.8Hz,1H),3.643.56(m,4H),2.542.47(m,2H),1.811.68(m,2H),1.58(m,2H),1.43–1.27(m,6H),0.97–0.88(m,3H),0.910.85(m,2H),0.83(d,J＝2.4Hz,17H),0.06–0.00(m,17H).
S7: synthesis of Compound of formula (10)
The compound of formula (9) (9.2 g,13.6 mmol), co 2(CO)8 (1.4 g,4.08 mmol), TMTU (0.54 g,4.08 mmol) was dissolved in 130mL of anhydrous toluene and stirred under carbon monoxide at 80℃until the reaction was complete. After the completion of the reaction, the mixture was cooled to room temperature, and purified by column chromatography to give the compound of formula (10) (8.2 g, 86%).
1H NMR(400MHz,CDCl3)δ7.22–7.13(m,2H),6.78(dd,J＝7.4,1.9Hz,1H),5.51(m,1H),4.95(s,2H),3.803.70(m,1H),3.60(t,J＝9.3Hz,2H),3.28–3.18(m,1H),3.07(dd,J＝12.9,8.9Hz,1H),3.00(dd,J＝13.0,11.8Hz,1H),2.51(m,2H),2.34(d,J＝8.2Hz,1H),2.22(d,J＝9.0Hz,1H),1.77(td,J＝9.7,8.2Hz,2H),1.56(m,2H),1.42–1.33(m,2H),1.371.27(m,4H),0.970.87(m,5H),0.84(d,J＝7.0Hz,18H),0.05(d,J＝6.4Hz,21H).
S8: synthesis of Compound of formula (11)
The compound of formula (10) (8.0 g,11.4 mmol), 10% Pd/C (20% w/w), anhydrous potassium carbonate (5% w/w) was dissolved in ethanol (100 mL), replaced with hydrogen and pressurized to 6bar, and stirred at 40℃until the reaction was complete. After the reaction, the mixture was cooled to room temperature, slowly depressurized, filtered, cooled to 0 ℃, 5M aqueous sodium hydroxide (23 mL) was added dropwise, stirred for half an hour, and then filtered and concentrated. After purification by column chromatography, the compound of formula (11) (5.5 g, 85%) was obtained.
1H NMR(400MHz,CDCl3)δ7.13(t,J＝8.1Hz,1H),6.90(M,1H),6.75(dd,J＝8.1,1.1Hz,1H),4.95(s,1H),3.71(p,J＝8.0Hz,1H),3.60(t,J＝9.3Hz,2H),3.00(dd,J＝13.0,8.9Hz,1H),2.78(dd,J＝13.0,11.4Hz,1H),2.722.59(m,2H),2.562.32(m,4H),2.30–2.18(m,1H),1.76–1.55(m,4H),1.59–1.47(m,2H),1.431.27(m,6H),0.97–0.86(m,5H),0.84(s,6H),0.05(d,J＝5.9Hz,14H).
S9: synthesis of Compound of formula (12)
The compound of formula (11) (5.0 g,8.7 mmol) was dissolved in ethanol (55 mL), sodium borohydride (1.0 g) was added in portions at 0deg.C, and the reaction was stirred until complete. The reaction mixture was quenched with acetic acid and extracted with ethyl acetate, and the organic phase was washed with 1M diluted hydrochloric acid and water, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give the compound of formula (12) (4.5 g, 90%).
1H NMR(400MHz,CDCl3)δ7.15(t,J＝8.1Hz,1H),6.83(m,1H),6.76(dd,J＝8.0,1.2Hz,1H),4.95(s,2H),3.96–3.87(m,1H),3.79(d,J＝6.7Hz,1H),3.723.61(m,1H),3.60(t,J＝9.3Hz,2H),2.84(dd,J＝13.0,8.6Hz,1H),2.75(dd,J＝13.0,11.0Hz,1H),2.652.52(m,2H),2.152.03(m,1H),2.031.92(m,2H),1.90(m,1H),1.70(m,1H),1.66–1.27(m,12H),0.970.88(m,3H),0.89(dt,J＝4.5,1.2Hz,2H),0.84(s,7H),0.05(d,J＝5.9Hz,15H).
S10: synthesis of Compound of formula (13)
A compound of formula (12) (4.0 g,6.93 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), tetrabutylammonium fluoride solution (1.0M, 17.3 mL) was added dropwise at 0deg.C, and the reaction was stirred at room temperature until completion. The mixture was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, purified by column chromatography, and the obtained product was recrystallized to give the compound of formula (13) (1.9 g, 83%).
1H NMR(MeOH,300MHz)δ0.89(t,3H,J)6Hz),1.1-2.30(m,19H),2.41-2.45(m,2H),2.64-2.78(m,2H),3.45-3.54(m,1H),3.55-3.81(m,1H),6.65(d,1H,J＝8Hz),6.73(d,1H,J＝8Hz),6.99(t,1H,J＝8Hz).
S11: synthesis of Compound of formula (1)
The compound of formula (13) (1.9 g,5.72 mmol) was dissolved in anhydrous acetonitrile (20 mL), anhydrous potassium carbonate (1.18 g,8.58 mmol) and bromoacetic acid were added at 0deg.C, stirred at room temperature until the reaction was complete, filtered, ethyl acetate was added, the organic phase was acidified with 4M hydrochloric acid and concentrated, and purified by column chromatography/recrystallization to give the compound of formula (1) (2.0 g, 90%).
1H NMR(CDCl3,300MHz)δ0.87(t,3H,J＝6Hz),1.21-1.86(m,13H),2.02-2.44(m,4H),3.42-3.76(m,3H),3.81(s,2H),3.82-3.94(m,1H),4.63-4.68(m,1H),4.88-4.92(m,1H),4.94-4.98(m,1H),4.99-5.02(m,1H),5.60(s,1H),5.92-6.06(m,1H),6.85(d,1H,J＝6Hz),7.20-7.27(m,1H),7.31-7.37(m,1H).
Example 2:
S1: synthesis of Compound of formula (3)
To a solution of the compound of formula (2) (50 g,128.5 mmol) in anhydrous toluene (210 mL) under nitrogen atmosphere was added azobisisobutyronitrile (5.8 g,35.3 mmol), followed by dropwise addition of tributylallyl tin (109.5 mL), and after completion of the dropwise addition, the reaction was allowed to stand at 80℃and TLC monitored for completion of the reaction. Acetonitrile (600 mL), water (60 mL) and potassium fluoride (40 g) were added and stirred overnight, celite was filtered, toluene was dried by spin-drying, acetonitrile and n-hexane were added and extracted three times, the acetonitrile phase was collected, washed with saturated brine, dried and concentrated, and the crude product (NMR purity 80%) was used directly in the next step.
1HNMR(400MHz,CDCl3)δ7.27(dt,J＝7.6,0.9Hz,1H),7.11(t,J＝7.8Hz,1H),6.85(dd,J＝8.0,1.2Hz,1H),5.91(m,1H),5.49(s,1H),5.16(d,J＝16.7Hz,2H),4.95(s,2H),3.91(m,4H),3.60(t,J＝9.3Hz,2H),3.55(d,J＝10.2Hz,2H),1.97(m,2H),0.93(t,J＝9.3Hz,2H),0.04(s,7H).
In this example, the steps S2 to S11 are exactly the same as in example 1.
Example 3:
S1: synthesis of Compound of formula (3)
The compound of formula (2) (50 g,128.5 mmol), tetrakis triphenylphosphine palladium (14.8 g,12.9 mmol) was added to 100mL of anhydrous toluene, tributylallyltin reagent (44 mL,141.8 mmol) was added under argon protection and reacted at 120℃under reflux, after TLC monitored the reaction to completion, cooled to room temperature, the catalyst was removed by suction filtration, ethyl acetate and water extracted filtrate, the organic phase was collected and purified by column layer separation (PE: EA 40:1-20:1) to give compound (3) (41 g, 90%).
1HNMR(400MHz,CDCl3)δ7.27(dt,J＝7.6,0.9Hz,1H),7.11(t,J＝7.8Hz,1H),6.85(dd,J＝8.0,1.2Hz,1H),5.91(m,1H),5.49(s,1H),5.16(d,J＝16.7Hz,2H),4.95(s,2H),3.91(m,4H),3.60(t,J＝9.3Hz,2H),3.55(d,J＝10.2Hz,2H),1.97(m,2H),0.93(t,J＝9.3Hz,2H),0.04(s,7H).
In this example, the steps S2 to S11 are exactly the same as in example 1.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. A process for the preparation of a compound of formula (4), comprising the steps of:
S1: subjecting a compound of the following formula (2) to allylation reaction, free radical allylation reaction or transition metal catalyzed coupling reaction to obtain a compound of the formula (3);
s2: hydrolyzing a compound of the following formula (3) to obtain a compound of the formula (4);
The reaction formula is as follows:
Wherein R 1 represents alkyl, alkoxy, alkylene oxide, alkoxyalkyl, alkylsilyl, arylsilyl, and, Any one of them; n and m independently represent an integer of 1 to 6; r 2 independently represents an alkyl group or an aryl group;
X represents halogen;
Pg represents R 3 independently represents an alkyl group, and n 1 represents an integer of 1 to 6.
2. The method according to claim 1, wherein the alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms; the alkoxy is straight-chain or branched-chain alkoxy with 1-6 carbon atoms; the epoxy alkyl is epoxy alkyl with 3-10 carbon atoms; the alkoxyalkyl group is an alkoxyalkyl group having 1 to 6 carbon atoms and 1 to 3 oxygen atoms; the aryl is a monocyclic or condensed ring aryl with 6-10 carbon atoms.
3. The method of claim 1, wherein the allylation reaction in step S1 comprises the steps of: under the action of a metal reagent, the compound of the formula (2) is converted into a corresponding Grignard reagent in a low-temperature aprotic solvent, and then the Grignard reagent reacts with allyl halohydrocarbon to obtain the compound of the formula (3).
4. A process according to claim 3, wherein,
The metal reagent is any one of methyl magnesium bromide, methyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride compound, n-butyl lithium, isobutyl lithium and tert-butyl lithium; n-butyllithium is preferred;
the low temperature is-80-0 ℃;
the aprotic solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, 2-butyl ether, 1, 4-dioxane and toluene; tetrahydrofuran is preferred;
the allyl halohydrocarbon is X is fluorine, chlorine, bromine or iodine; preferably, the allyl halogenated hydrocarbon is allyl chloride, allyl bromide, allyl iodide; more preferably, the allylic halogenated hydrocarbon is allylic bromine.
5. The method of claim 1, wherein the radical allylation reaction in step S1 comprises the steps of: reacting the compound of formula (2) with trialkyl allyl tin under the action of a free radical initiator to obtain the compound of formula (3).
6. The method according to claim 5, wherein,
The free radical initiator is azodiisobutyronitrile;
The trialkyl allyl tin is any one of trimethyl allyl tin, triethyl allyl tin and tri-n-butyl allyl tin; preferably tri-n-butyl allyl tin;
the solvent used in the reaction is an alkane solvent, a benzene solvent or an ether solvent; preferably, the alkane solvent is cyclohexane; the benzene solvent is toluene; the ether solvent is tetrahydrofuran;
the reaction temperature is 30-100 ℃; preferably 60-80 ℃.
7. The method of claim 1, wherein the transition metal catalyzed coupling reaction in step S1 comprises the steps of: the compound of formula (2) reacts with a transition metal catalyst and a ligand to form the compound of formula (3) with a trialkyl allyl tin reagent under the anaerobic condition.
8. The method according to claim 7, wherein,
The transition metal catalyst is a palladium catalyst; tetrakis (triphenylphosphine) palladium, pdCl 2(PPh3)2、PdCl2(MeCN)2, or Pd 2(dba)3 are preferred; more preferably tetrakis (triphenylphosphine) palladium;
the ligand is an organic phosphine ligand; triphenylphosphine is preferred;
The trialkyl allyl tin reagent is any one of trimethyl allyl tin, triethyl allyl tin and tri-n-butyl allyl tin; preferably tri-n-butyl allyl tin;
the solvent used in the reaction is benzene solvent, ether solvent or amide solvent; the benzene solvent is preferably toluene; the ether solvent is preferably 1, 4-dioxane; the amide solvent is preferably N, N-dimethylformamide;
The reaction temperature is 30℃to 150℃and preferably 80℃to 120 ℃.
9. The process according to claim 1, wherein the compound of formula (3) is hydrolyzed in step S2 under acid and solvent conditions to give the compound of formula (4).
10. A process for preparing treprostinil using a compound of formula (4), comprising the steps of:
S1: reacting a compound of the following formula (5) with a compound of the formula (4) under the action of a metal reagent to obtain a compound of the formula (6);
S2: carrying out hydroxyl oxidation on a compound of the following formula (6) to obtain a compound of the formula (7);
S3: carrying out asymmetric reduction on a compound of the following formula (7) to obtain a compound of the formula (8);
s4: hydroxy protecting the compound of the following formula (8) to obtain a compound of the formula (9);
S5: a compound of the following formula (9) is subjected to ring closure reaction under the atmosphere of a transition metal catalyst and carbon monoxide to obtain a compound of the following formula (10);
S6: carrying out catalytic hydrogenation on a compound of the following formula (10) to obtain a compound of the following formula (11);
s7: carbonyl reduction is carried out on the compound of the following formula (11) to obtain a compound of the following formula (12);
S8: removing a protecting group from a compound of the following formula (12) to obtain a compound of the following formula (13);
s9: carrying out caproic acid modification reaction on the compound of the following formula (13) to obtain a compound of the formula (1), namely treprostinil;
The reaction formula is as follows:
Wherein R 1 and Pg are as defined in claim 1;
pg 2 and Pg 3 independently represent alkyl, alkoxy, alkylene oxide, alkoxyalkyl, alkylsilyl, arylsilyl, and, Any one of them; n and m independently represent an integer of 1 to 6; r 2 independently represents an alkyl group or an aryl group.
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