CN117843599A - Preparation method of prostaglandin intermediate containing 1-alkyl-1-alkenyl ethanol structure - Google Patents
Preparation method of prostaglandin intermediate containing 1-alkyl-1-alkenyl ethanol structure Download PDFInfo
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- CN117843599A CN117843599A CN202211208287.8A CN202211208287A CN117843599A CN 117843599 A CN117843599 A CN 117843599A CN 202211208287 A CN202211208287 A CN 202211208287A CN 117843599 A CN117843599 A CN 117843599A
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- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 229940125898 compound 5 Drugs 0.000 claims abstract description 10
- 230000009471 action Effects 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 22
- -1 t-butyldiphenylsilyl Chemical group 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 11
- 238000006772 olefination reaction Methods 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000007254 oxidation reaction Methods 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 150000002596 lactones Chemical class 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims 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 claims description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- UOWIYNWMROWVDG-UHFFFAOYSA-N 1-dimethoxyphosphorylpropan-2-one Chemical group COP(=O)(OC)CC(C)=O UOWIYNWMROWVDG-UHFFFAOYSA-N 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- RSAFKRSMGOSHRK-UHFFFAOYSA-N 1-diethoxyphosphorylpropan-2-one Chemical compound CCOP(=O)(CC(C)=O)OCC RSAFKRSMGOSHRK-UHFFFAOYSA-N 0.000 claims description 2
- MXJGZAMERDEUKM-UHFFFAOYSA-N N[Li].C[Si](N[Si](C)(C)C)(C)C Chemical compound N[Li].C[Si](N[Si](C)(C)C)(C)C MXJGZAMERDEUKM-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- QFIRONPERRUJAN-UHFFFAOYSA-N [NH2-].[Na+].C[Si](N[Si](C)(C)C)(C)C Chemical compound [NH2-].[Na+].C[Si](N[Si](C)(C)C)(C)C QFIRONPERRUJAN-UHFFFAOYSA-N 0.000 claims description 2
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 2
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 2
- 150000004795 grignard reagents Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 13
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000011925 1,2-addition Methods 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001308 synthesis method Methods 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- UMMADZJLZAPZAW-OVXHCKHTSA-N carboprost tromethamine Chemical compound OCC([NH3+])(CO)CO.CCCCC[C@](C)(O)\C=C\[C@H]1[C@@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC([O-])=O UMMADZJLZAPZAW-OVXHCKHTSA-N 0.000 description 5
- 229960005296 carboprost tromethamine Drugs 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- OWVIRVJQDVCGQX-NSOVKSMOSA-N [(4s,5s)-5-[hydroxy(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)([C@@H]1[C@H](OC(O1)(C)C)C(O)(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OWVIRVJQDVCGQX-NSOVKSMOSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- KPDGHZVTMOQSHV-UHFFFAOYSA-N CCCCC[Zn] Chemical compound CCCCC[Zn] KPDGHZVTMOQSHV-UHFFFAOYSA-N 0.000 description 3
- 208000018525 Postpartum Hemorrhage Diseases 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- PXGPLTODNUVGFL-UHFFFAOYSA-N prostaglandin F2alpha Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CC=CCCCC(O)=O PXGPLTODNUVGFL-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960003395 carboprost Drugs 0.000 description 2
- DLJKPYFALUEJCK-MRVZPHNRSA-N carboprost Chemical compound CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C\CCCC(O)=O DLJKPYFALUEJCK-MRVZPHNRSA-N 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- KPSZWAJWFMFMFF-UHFFFAOYSA-N hept-5-enoic acid Chemical compound CC=CCCCC(O)=O KPSZWAJWFMFMFF-UHFFFAOYSA-N 0.000 description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RIAKDKCWGIVRRH-UHFFFAOYSA-N 2-bromopentanoic acid triphenylphosphane Chemical compound CCCC(Br)C(O)=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIAKDKCWGIVRRH-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010021718 Induced labour Diseases 0.000 description 1
- 208000034702 Multiple pregnancies Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003509 anti-fertility effect Effects 0.000 description 1
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- XWCQLLDGXBLGMD-UHFFFAOYSA-M magnesium;pentane;bromide Chemical compound [Mg+2].[Br-].CCCC[CH2-] XWCQLLDGXBLGMD-UHFFFAOYSA-M 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005070 ripening Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a prostaglandin intermediate (compound 5) containing a 1-alkyl-1-alkenyl ethanol structure, which is obtained by taking alpha, beta-unsaturated methyl ketone as a substrate, and carrying out asymmetric 1, 2-addition through the action of an alkyl metal reagent and a chiral ligand. The method of the invention changes the traditional addition without selectivity, has simple operation, higher yield, is suitable for industrial production, and has higher application value for preparing prostaglandin intermediates containing the structure.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a prostaglandin intermediate containing a 1-alkyl-1-alkenyl ethanol structure.
Background
Carboprostaglandin is a C-15 methyl analog of prostaglandin F2 alpha (prostaglandin F2 alpha), chemically named (Z) -7- [ (3R, 5S) -3, 5-dihydroxy-2- [ (E, 3S) -3-hydroxy-3-methyl-oct-1-enyl]Cyclopentyl group]Hept-5-enoic acid. The molecular formula: c (C) 21 H 36 O 5 Molecular weight 368.51.
Early postpartum hemorrhage is a major cause of perinatal complications and increased mortality, and is also one of the serious complications of obstetrics. When the puerpera is combined with factors such as advanced age, multiple pregnancy, uterine contractility and the like, bleeding is very easy in production, and prostaglandin is a bioactive substance with wide physiological effects and has various important physiological regulation functions, wherein prostaglandin F2 alpha has the effect of contracting smooth muscle and can effectively prevent postpartum hemorrhage. The carboprostaglandin has lasting effect, can delay dehydrogenation and inactivation in vivo, has effects of softening and dilating cervix, increasing uterine contraction frequency and contraction amplitude, enhancing uterine contraction, and has strong antifertility effect. The injection is used for promoting cervical ripening and induced labor in midterm pregnancy abortion and late term pregnancy. Can avoid emergency operation, has important significance for reducing the occurrence rate of postpartum hemorrhage and the death rate of high-risk pregnant and lying-in women, and is an irreplaceable product in the current clinical medicine.
However, the synthesis methods of prostaglandin analogues reported so far are less, the conditions are harsh, and the yield is low. In particular, the construction of quaternary chiral tertiary alcohols in the lower chain is very challenging. For example, patent CN110117242A discloses a process for the preparation of carboprost tromethamine, which involves the following main intermediate structure,
the method takes the coriolis lactone as a raw material, and reacts with alkyl silicon chloride under the action of alkali to obtain a compound 2; reacting the compound 2 with an oxidant to obtain a compound 3; reacting the compound 3 with beta-carbonyl dimethoxy heptyl phosphate under the action of alkali to obtain a compound 4; the compound 4 reacts with a methyl Grignard reagent and reacts with alkyl silicon chloride under the action of alkali to obtain a compound 5; reacting the compound 5 with a reducing agent to obtain a compound 6; reacting the compound 6 with bromopentanoic acid triphenylphosphine salt under the action of alkali to obtain a compound 7; the compound 7 is subjected to a reaction of removing the alkyl silicon protecting group R under the action of acid to obtain the carboprost; the carboprost reacts with the trometamol to obtain the carboprost tromethamine.
As another example, patent CN111777537a discloses a method for preparing carboprost tromethamine, which comprises the following steps:
the preparation methods disclosed in the two patents are similar and relate to the preparation of intermediatesIs carried out by a method comprising the steps of. And is>Further preparation of->The process of (2) often requires longer reaction time and lower reaction yield, the chiral center selectivity ratio produced is poor, complicated purification steps are required, and the separation of isomer impurities produced in mass production is difficult, which is not beneficial to industrial production.
In view of the foregoing, there is a need in the art to develop a process for preparing carboprost tromethamine that is easy to operate, low in production cost, high in yield, and suitable for industrial production.
Disclosure of Invention
The invention aims to: the invention aims to provide a preparation method of a prostaglandin intermediate containing a 1-alkyl-1-alkenyl ethanol structure, which is simple and convenient to operate, low in production cost, high in yield and suitable for industrial production.
The technical scheme is as follows: the invention relates to a preparation method of a prostaglandin intermediate containing a 1-alkyl-1-alkenyl ethanol structure, wherein the chemical structural formula of the prostaglandin intermediate is shown as a general formula (5), and the preparation method of the prostaglandin intermediate comprises the following steps:
(1) The coriolis lactone 2 undergoes an oxidation reaction to form compound 3;
(2) Compound 3 is converted to compound 4 by HWE olefination;
(3) Reacting the compound 4 under the action of a Grignard reagent to form a compound 5;
the reaction formula of the preparation method is as follows:
in the above formula, pg is a protecting group.
In some embodiments of the invention, the protecting group Pg is R 1-1 R 1-2 R 1-3 Si-、-C(O)R 1-4 、-(C 1-4 Alkoxy) -CHR 1-5 -R 1-6 H or THP (2-tetrahydropyran).
In some embodiments of the invention, preferably, the R 1 Is R 1-1 R 1-2 R 1-3 Si-, said R 1 Selected from t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl, trimethylsilyl or triisopropylsilyl; the R is 1 is-C (O) R 1-4 When said R is 1-4 Substituted aryl or unsubstituted aryl of C6-10; the substituent of the substituted aryl is selected from halogen, cyano, trifluoromethyl, nitro, hydroxyl and the like; more preferably, the R 1-4 Unsubstituted aryl of C6-10; the R is 1 Is- (C) 1-4 Alkoxy) -CHR 1-5 -R 1-6 When said R is 1-5 And R is 1-6 Independently hydrogen or methyl.
Step (1) of the method of the invention:
the oxidation reaction is carried out in the presence of an oxidizing agent which is 2-iodoxybenzoic acid (IBX), dess-martin oxidizing agent, active manganese dioxide, sodium hypochlorite, PCC (pyridinium chlorochromate) or PDC (pyridinium dichromate); the preferred oxidizing agent is dess-martin oxidizing agent;
according to one embodiment of the invention, the oxidation reaction is carried out in the presence of a solvent, which is one or more of acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethyl acetate, ethanol, dimethyl sulfoxide, isopropanol, N' -dimethylformamide, preferably dichloromethane;
according to one embodiment of the invention, the molar ratio of the coriolis lactone 2 to the oxidizing agent is 1:1-5; the preferable molar ratio is 1:1-2; according to another embodiment of the present invention, the temperature of the oxidation reaction is 0 to 100 ℃; the preferable reaction temperature is 20-40 ℃; the time of the oxidation reaction is 0.5-2 h; preferably 0.5 to 1h.
Step (2) of the method of the invention:
the HWE reaction is carried out in the presence of an olefination reagent and a base, wherein the olefination reagent is one of dimethyl acetonylphosphonate or diethyl acetonylphosphonate; the alkali is one or more of hexamethyldisilazane lithium amide, hexamethyldisilazane sodium amide, hexamethyldisilazane potassium amide, sodium hydride, potassium tert-butoxide, n-butyllithium, triethylamine, diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably sodium hydride;
according to one embodiment of the present invention, the HWE olefination is carried out in the presence of a solvent, which is one or more of acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethyl acetate, ethanol, dimethyl sulfoxide, isopropanol, N' -dimethylformamide, toluene, preferably tetrahydrofuran;
according to one embodiment of the invention, the molar ratio of the compound 3, the olefination reagent and the alkali is 1:1-5:1-5; preferably 1:1 to 3:1 to 3; according to one embodiment of the present invention, the HWE olefination reaction has a reaction temperature of-78 to 0 ℃; preferably-20 to 0 ℃; the reaction time is 1 to 5 hours, preferably 2 to 3 hours.
Step (3) of the method of the invention:
the reaction is carried out in the presence of a chiral ligand and a metal alkyl reagent; the chiral ligand is as follows:(Szulfonamide)，/>(S and R)-Taddol，/>(S and R)-BINAL，(MIB)；/>(DAIB)，/>etc.; the alkyl metal reagent comprises alkyl magnesium halide, alkyl lithium, alkyl zinc and the like;
according to one embodiment of the invention, the reaction is carried out in the presence of a solvent, which is one or more of acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethyl acetate, ethanol, dimethyl sulfoxide, isopropanol, N' -dimethylformamide, preferably tetrahydrofuran and toluene;
according to one embodiment of the invention, the molar ratio of the compound 4, the chiral ligand and the alkyl metal reagent is 1:0.05-0.5:1-10; preferably 1:0.1-0.3:2-5; according to one embodiment of the invention, the reaction temperature is-80 to 0 ℃.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: the invention takes cheap and easily available coriolis lactone as the initial raw material, and is synthesized by 3 steps of reactions. The synthetic route has simple and convenient operation, higher yield, easy control of reaction and suitability for industrial production. Compared with the existing route, the synthesis method has the advantages that the isomer ratio is high, the product purity is high, the separation is easy, the yield is high, and the isomer impurities are effectively reduced when the intermediate is synthesized. Providing a great assistance for the preparation of prostaglandin products (such as carboprost tromethamine and the like) containing the structure.
Detailed Description
The technical scheme of the invention is further described below.
The synthesis of the prostaglandin intermediate (Compound 5) having a 1-alkyl-1-alkenylethanol structure according to the present invention will be described in further detail with reference to the following examples.
In the examples of the present invention, the route for synthesizing a prostaglandin intermediate having a 1-alkyl-1-alkenylethanol structure using as the starting material, the following is shown:
wherein the protecting group Pg is R 1-1 R 1-2 R 1-3 Si-、-C(O)R 1-4 、-(C 1-4 Alkoxy) -CHR 1-5 -R 1-6 H or THP (2-tetrahydropyran); the R is 1 Is R 1-1 R 1-2 R 1-3 Si-, said R 1 Selected from t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl, trimethylsilyl or triisopropylsilyl; the R is 1 is-C (O) R 1-4 When said R is 1-4 Substituted aryl or unsubstituted aryl of C6-10; the substituent of the substituted aryl is selected from halogen, cyano, trifluoromethyl, nitro, hydroxyl and the like; more preferably, the R 1-4 Unsubstituted aryl of C6-10; the R is 1 Is- (C) 1-4 Alkoxy) -CHR 1-5 -R 1-6 When said R is 1-5 And R is 1-6 Independently hydrogen or methyl.
The examples were conducted under conventional conditions, except that the specific conditions were not specified. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. In addition, the technical solutions of the embodiments may be combined with each other, but it is necessary to base that the technical solutions can be realized by those skilled in the art, and when the technical solutions are contradictory or cannot be realized, the combination of the technical solutions should be considered to be absent and not within the scope of protection claimed in the present invention.
Example 1
The present example provides a method for synthesizing compound 3:
compound 1 (5.0 g,18.1 mmol), dess-martin oxidant (10.2 g,36.4 mmol) were dissolved in anhydrous dichloromethane (60 mL), the reaction was reacted at room temperature for 40min, silica gel was filtered, concentrated, and column chromatography gave compound 3 (4.9 g, 99%).
1H NMR(500MHz,Chloroform-d)：δ9.52(dt,J＝7.4,1.9Hz,1H),8.04-7.97(m,2H),7.59-7.52(m,1H),7.48-7.41(m,2H),5.28-5.21(m,1H),5.04(ddddt,J＝7.9,7.0,6.0,1.7,0.8Hz,1H),3.01-2.87(m,2H),2.70(d,J＝8.1Hz,1H),2.59(d,J＝8.8Hz,1H),2.39(ddd,J＝12.8,7.1,5.5Hz,1H),2.29(ddd,J＝13.0,7.9,6.2Hz,1H)。
Example 2
The present example provides a method for the synthesis of compound 4:
dimethyl acetonylphosphonate (3.33 g,20.05 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under nitrogen protection, sodium hydride (1.1 eq) was added in portions at 0deg.C, the reaction was stirred at 0deg.C for 1h, then a tetrahydrofuran solution (20 mL) of compound 3 (5 g,18.23 mmol) was slowly added dropwise, and the reaction was continued for 1.5h. Saturated ammonium chloride solution (20 mL) was added to quench, the solvent was removed under reduced pressure, extracted with ethyl acetate (3X 100 mL), washed with saturated sodium chloride (2X 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed to give compound 4 (5.3 g, 92%).
1H NMR(500MHz,Chloroform-d)：δ7.95–7.88(m,2H),7.58(ddt,J＝9.0,7.1,1.5Hz,1H),7.49–7.41(m,2H),6.77(dd,J＝16.1,7.0Hz,1H),5.95(dd,J＝16.1,0.9Hz,1H),4.96(td,J＝5.4,4.2Hz,1H),4.90(td,J＝5.0,4.2Hz,1H),2.88(dddd,J＝7.3,6.4,5.4,1.0Hz,1H),2.66(d,J＝5.5Hz,2H),2.53–2.40(m,2H),2.27(s,2H),2.13(dt,J＝14.5,4.0Hz,1H).
Example 3
This example provides a compound 5The synthesis method of (2):
(4S, 5S) - (2, 2-dimethyl-1, 3-dioxolan-4, 5-diyl) bis (diphenylmethanol) (Taddol) (4.45 g,9.54 mmol) was dissolved in toluene (50 mL) under nitrogen protection at-20deg.C, a tetrahydrofuran solution of pentylzinc (33.4 mL, 1M) was added thereto, and after stirring at-20deg.C for 30min, a tetrahydrofuran solution (40 mL) of Compound 4 (3 g,9.54 mmol) was added thereto, and the reaction was continued at-20 to 0deg.C for 24 hours. Saturated ammonium chloride solution (30 mL) was added to quench, the solvent was removed under reduced pressure, extracted with ethyl acetate (3X 100 mL), washed with saturated sodium chloride (2X 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed to give compound 5 (3.5 g, 94%)
1H NMR (500 MHz, chloroform-d, major isomer): delta 7.95-7.88 (m, 2H), 7.59 (ddt, j=9.0, 7.1,1.5hz, 1H), 7.50-7.42 (m, 2H), 5.52 (d, j=3.0 hz, 2H), 4.98 (td, j=5.3, 4.1hz, 1H), 4.91-4.84 (m, 1H), 3.40 (s, 1H), 2.65-2.52 (m, 3H), 2.47-2.38 (m, 2H), 2.11 (dt, j=14.5, 4.2hz, 1H), 1.70-1.61 (m, 1H), 1.55-1.46 (m, 1H), 1.40-1.27 (m, 4H), 1.26 (s, 2H), 1.31-1.15 (m, 2H), 0.91-0.83 (m, 3H).
Example 4
This example provides a compound 5The synthesis method of (2):
(4S, 5S) - (2, 2-dimethyl-1, 3-dioxolan-4, 5-diyl) bis (diphenylmethanol) (Taddol) (4.2 g,9 mmol) was dissolved in toluene (50 mL) under nitrogen protection at-78deg.C, a solution of compound 4 (2.8 g,9 mmol) in tetrahydrofuran (40 mL) was added followed by dropwise addition of a solution of pentylmagnesium bromide (2.0 eq) at-78deg.C and reaction continued for 24h. Quenched by addition of saturated ammonium chloride solution (30 mL), the solvent was removed under reduced pressure, extracted with ethyl acetate (3X 100 mL), washed with saturated sodium chloride (2X 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed to give compound 5 (2.7 g, 72%)
Example 4
This example provides a compound 5The synthesis method of (2):
(4S, 5S) - (2, 2-dimethyl-1, 3-dioxolan-4, 5-diyl) bis (diphenylmethanol) (Taddol) (4.45 g,9.54 mmol) was dissolved in toluene (50 mL) under nitrogen protection at-20deg.C, a tetrahydrofuran solution of pentylzinc (33.4 mL, 1M) was added thereto, and after stirring at-20deg.C for 30min, a tetrahydrofuran solution (40 mL) of Compound 4 (3 g,9.54 mmol) was added thereto, and the reaction was continued at-20 to 0deg.C for 24 hours. Quenched by addition of saturated ammonium chloride solution (30 mL), the solvent was removed under reduced pressure, extracted with ethyl acetate (3X 100 mL), washed with saturated sodium chloride (2X 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed to give compound 5 (3.4 g, 90%)
Example 5
This example provides a compound 5The synthesis method of (2):
(4S, 5S) - (2, 2-dimethyl-1, 3-dioxolan-4, 5-diyl) bis (diphenylmethanol) (Taddol) (2 g,4.3 mmol) was dissolved in toluene (20 mL) under nitrogen protection at-20deg.C, while a tetrahydrofuran solution of pentylzinc (15 mL, 1M) was added, and after stirring at-20deg.C for 30min, a tetrahydrofuran solution (15 mL) of Compound 4 (1.3 g,4.3 mmol) was added, and the reaction was continued at-20-0deg.C for 24h. Quenched by addition of saturated ammonium chloride solution (20 mL), the solvent was removed under reduced pressure, extracted with ethyl acetate (3X 50 mL), washed with saturated sodium chloride (2X 50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed to give compound 5 (1.4 g, 89%)
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 (9)
1. A method for preparing a prostaglandin intermediate containing a 1-alkyl-1-alkenyl ethanol structure, which is characterized in that the chemical structural formula of the prostaglandin intermediate is shown as a general formula (5), and the preparation method of the prostaglandin intermediate comprises the following steps:
(1) The coriolis lactone 2 undergoes an oxidation reaction to form compound 3;
(2) Compound 3 is converted to compound 4 by HWE olefination;
(3) Reacting the compound 4 under the action of a Grignard reagent to form a compound 5;
the reaction process of the preparation method is as follows:
in the above formula, pg is a protecting group.
2. The method for producing a prostaglandin intermediate having a 1-alkyl-1-alkenylethanol structure according to claim 1, wherein Pg is R 1-1 R 1-2 R 1-3 Si-、-C(O)R 1-4 、-(C 1-4 Alkoxy) -CHR 1-5 -R 1-6 H or THP; the R is 1 Is R 1 -1 R 1-2 R 1-3 Si-, said R 1 Selected from t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl, trimethylsilyl or triisopropylsilyl; the R is 1 is-C (O) R 1-4 When said R is 1-4 Substituted aryl or unsubstituted aryl of C6-10; the substituent of the substituted aryl is selected from halogen, cyano, trifluoromethyl, nitro or hydroxy; the R1 is- (C) 1-4 Alkoxy) -CHR 1-5 -R 1-6 When said R is 1-5 And R is 1-6 Independently hydrogen or methyl.
3. The process for preparing a prostaglandin intermediate having a 1-alkyl-1-alkenylethanol structure according to claim 1 or 2, wherein in step (1), the oxidation reaction is performed in the presence of an oxidizing agent, which is 2-iodoxybenzoic acid (IBX), dess-martin oxidizing agent, active manganese dioxide, sodium hypochlorite, PCC or PDC.
4. The process for producing a prostaglandin intermediate having a 1-alkyl-1-alkenylethanol structure according to claim 3, wherein in the step (1), the molar ratio of the coriolis lactone 2 to the oxidizing agent is 1:1 to 5; the temperature of the oxidation reaction is 0-100 ℃; the time of the oxidation reaction is 0.5-2 h.
5. The process for the preparation of a prostaglandin intermediate having a 1-alkyl-1-alkenylethanol structure according to claim 1 or 2, wherein in step (2), the HWE olefination reaction is carried out in the presence of phosphate and base, and the olefination reagent is dimethyl acetonylphosphonate, diethyl acetonylphosphonate; the alkali is one or more of hexamethyldisilazane lithium amide, hexamethyldisilazane sodium amide, hexamethyldisilazane potassium amide, sodium hydride, potassium tert-butoxide, n-butyllithium, triethylamine, diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
6. The process for producing a prostaglandin intermediate having a 1-alkyl-1-alkenylethanol structure according to claim 5, wherein in step (2), the molar ratio of the compound 3, the olefination reagent and the base is 1:1 to 5:1 to 5; the reaction temperature of the HWE olefination reaction is-78-0 ℃; the reaction time is 1-5h.
7. The process for producing a prostaglandin intermediate having a 1-alkyl-1-alkenylethanol structure according to claim 1 or 2, wherein in step (3), the reaction is carried out in the presence of a metal alkyl reagent and a chiral ligand; the alkyl metal reagent comprises alkyl magnesium halide, alkyl lithium, alkyl zinc and the like; chiral ligands(Szulfonamide)，(S and R)-Taddol，/>(S and R)-BINAL，/>(MIB)；/>(DAIB)，/>
8. The process for producing a prostaglandin intermediate having a 1-alkyl-1-alkenylethanol structure according to claim 7, wherein in the step (3), the molar ratio of the compound 4, the chiral ligand and the metal alkyl agent is 1:0.05-0.5:1-10; the reaction temperature is-80-0 ℃.
9. The process for producing a prostaglandin intermediate having a 1-alkyl-1-enyl ethanol structure according to claim 1 or 2, wherein the reactions of step (1) to step (3) are carried out in the presence of a solvent, and the solvent of each step is independently selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethyl acetate, ethanol, dimethyl sulfoxide, isopropanol, and N, N' -dimethylformamide.
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