CN112645861A - Method for separating carboprost 15-position isomer - Google Patents
Method for separating carboprost 15-position isomer Download PDFInfo
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- CN112645861A CN112645861A CN202011519386.9A CN202011519386A CN112645861A CN 112645861 A CN112645861 A CN 112645861A CN 202011519386 A CN202011519386 A CN 202011519386A CN 112645861 A CN112645861 A CN 112645861A
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- Prior art keywords
- carboprost
- compound
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- separating
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- 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 title claims abstract description 47
- 229960003395 carboprost Drugs 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000000926 separation method Methods 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- -1 hydroxyl tertiary alcohol Chemical class 0.000 claims abstract description 16
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 11
- QQCOAAFKJZXJFP-XAYIDPIISA-N 15-methyl-15R-PGF2alpha methyl ester 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)OC QQCOAAFKJZXJFP-XAYIDPIISA-N 0.000 claims description 10
- 229940126062 Compound A Drugs 0.000 claims description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- 239000007818 Grignard reagent Substances 0.000 claims description 5
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical group [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 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 claims description 3
- 229960005296 carboprost tromethamine Drugs 0.000 claims description 3
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000010898 silica gel chromatography Methods 0.000 abstract description 7
- 239000012535 impurity Substances 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 3
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- 238000001914 filtration Methods 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 150000003180 prostaglandins Chemical class 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 150000003509 tertiary alcohols Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000003223 protective agent Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 229960000281 trometamol Drugs 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 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 1
- GMWTXQKKRDUVQG-WOPPDYDQSA-N 4-amino-5-bromo-1-[(2r,3s,4s,5r)-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidin-2-one Chemical compound C[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C(Br)=C1 GMWTXQKKRDUVQG-WOPPDYDQSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021718 Induced labour Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- GTTSNKDQDACYLV-UHFFFAOYSA-N Trihydroxybutane Chemical compound CCCC(O)(O)O GTTSNKDQDACYLV-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- KZIBQYUFIVUOHY-UHFFFAOYSA-N bis(2-methylpropyl)alumane toluene Chemical compound Cc1ccccc1.[H][Al](CC(C)C)CC(C)C KZIBQYUFIVUOHY-UHFFFAOYSA-N 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Substances CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- 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 separation technical method of 15-bit isomer impurities of caprostaglandin, belonging to the technical field of medicinal chemistry separation. And (3) performing PG protection on the compound B with 15-site hydroxyl tertiary alcohol to obtain 15-site S-type carboprost D and 15-site R-type carboprost E (forming a 15-site hydroxyl tertiary alcohol compound C), and separating to obtain a pure product of the 15-site carboprost D or the 15-site carboprost E. On the basis, the invention also provides a method for preparing carboprost series products suitable for industrial scale-up. The method can separate isomers by adopting common silica gel column chromatography after being derived by a proper protecting group, has simple operation, meets the requirement on the quality of the obtained product, greatly reduces the production cost and improves the comprehensive benefit of the product.
Description
Technical Field
The invention relates to the technical field of medicinal chemical separation, in particular to a novel technical method for separating impurities of a caprostaglandin 15-position tertiary alcohol R isomer.
Background
Prostaglandins (PGs) are important endogenous products with a wide range of physiological activities. PGs are present in almost all mammalian tissues, play an important role in the reproductive, digestive, respiratory and cardiovascular systems, and are involved in physiological and pathological processes such as thermoregulation, inflammatory responses, glaucoma, pregnancy, hypertension, ulcers and asthma.
The structural characteristics of PGs are as follows: has a five-membered alicyclic ring and two side chains, wherein the upper chain generally has 7 carbons, and the lower side chain has 8 carbons to form 20-carbon unsaturated fatty acid and the like. PGs were first discovered and named by Von Eluer, american scholars, in 1930, and Bergstorm, 1962, extracted two pure forms of PG (PGFl and PGF2) and determined their chemical structures. In 1969 Willis first proposed that PGs is an inflammatory mediator in the body. Subsequently, various physiological activities and pharmacological activities of PGs were intensively studied.
Prostaglandins have the defects of few natural sources, difficult extraction, rapid in vivo metabolism, poor stability and the like, so scientists synthesize a series of prostaglandin substances or analogues successively and completely to meet clinical requirements.
The traditional Chinese medicine composition is successfully applied to induced labor, induction of birth and induced abortion in clinic at present, and the marketed medicines comprise: carboprost (1), carboprost methyl ester (2), carboprost tromethamine (3), etc., whose structures are represented as follows:
the synthesis strategy of carboprost is to utilize a key intermediate Corey lactone to respectively graft an upper side chain and a lower side chain at alpha and omega positions, and a typical synthesis reaction route is as follows:
in 1974, carboprost methyl ester was first synthesized by Ernest W.yankee (J.Am.chem.Soc.,1974,96, 5865-; similar synthetic methods are also reported in Pranav Patel (j. org. chem.2008,73, 7213-: separation of 15R isomers of carglactin methyl ester is carried out by performing high-efficiency preparative chromatography column chromatography in the penultimate step, so that the capacity is greatly limited, and the production efficiency is influenced; in WO2017093770 a1, however, it was reported that 15R isomer was removed by column chromatography using chromatoreexmb type silica gel having a particle size of 40 to 70 μm, with a yield of only 57%. The chiral filler in the method is expensive, the production cost is greatly increased, and the industrial large-scale application of the chiral filler is limited. Patent CN 1136938C discloses the use of simulated moving bed chromatography (SMBC for short) to separate cardprost methyl ester, the method has high equipment investment, is not suitable for industrial production, and the separation purity is only 90%, which cannot meet the requirements of pharmacopoeia on isomers.
Patent CN110746333A in 2019 reports that separation is carried out by using D-camphorsulfonyl chloride as a chiral resolving agent, and the reaction equation is as follows:
the selectivity of hemiacetal hydroxyl and 15-site tertiary hydroxyl is to be verified, and meanwhile, the biphenyl formyl exists in the molecule and the chiral camphor sulfonyl is introduced, so that the whole molecule is more complex, the yield of three steps is only about 17%, and the difficulty and uncertainty are brought to subsequent industrial mass production.
Along with the expansion of the drug effect of the carboplatin, the carboplatin is favored by more and more manufacturers, and has great market potential. Therefore, the existing synthesis process is optimized, the yield is improved, the cost is reduced, and great practical significance and economic value are achieved; meanwhile, a more simple and feasible large-scale production process is designed, market first opportunity is obtained, the method is one of the focuses of researching the prostaglandin synthesis process, and the method has extremely important significance in filling up the process blank and creating economic value.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: after a proper protecting group is introduced into the 15-position hydroxyl isomer produced by the prior art, the 15-position hydroxyl isomer can be removed by a simple purification method (such as column chromatography) so as to remarkably improve the yield and the degree of difficulty in operation and improve the product quality, thereby enhancing the competitiveness of products of companies. On the basis, the invention also provides a method for preparing carboprost series products suitable for industrial scale-up.
The invention relates to a method for separating carboprost 15 isomer, which is technically characterized in that: and (3) performing PG protection on the compound B with 15-site hydroxyl tertiary alcohol to obtain 15-site S-type carboprost D and 15-site R-type carboprost E (forming a 15-site hydroxyl tertiary alcohol compound C), and separating to obtain a 15-site S-type carboprost D pure product and a 15-site R-type carboprost E pure product.
Wherein, R is THP, TES, TBS, Bz and Bn.
Further, in the above technical scheme, the PG protection is selected from benzoyl, trityl, triethylsilicon, acetyl, p-toluenesulfonyl, benzyl, and the like. Under the optimized condition, the acetyl is most ideal in separation effect.
Further, in the above technical scheme, the Rf difference during the separation is above 0.05, and column chromatography, thin-layer chromatography, HPLC preparative column, etc. are used for the separation. Preferably, column chromatography is used for separation.
On the basis of the separation scheme, the invention also provides a preparation method of carboprost, which comprises the following steps: carrying out addition reaction on the compound A and a methyl Grignard reagent at low temperature to obtain a compound B; protecting the compound B with acetyl to obtain a compound C1; separating the compound C1 by column chromatography to obtain 15S carboprost D1; 15S carboprost D1 to obtain compound F; the compound F is subjected to a Witig reaction to obtain carboprost 1. The following equation is used:
further, in the above technical solution, the first step methyl grignard reagent is selected from methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
Further, in the technical scheme, the first-step reaction solvent is one or more of THF, 2-MeTHF or toluene; the reaction temperature is 0 ℃ or lower, preferably-50 ℃ or lower.
Further, in the above technical scheme, the acetyl protection in the second step is performed by using acetyl chloride or acetic anhydride under the condition of triethylamine, pyridine or diisopropylethylamine.
Furthermore, in the technical scheme, DIBAL-H is adopted for reduction in the third step, acetyl is also removed at the same time, and additional hydrolysis is not needed.
Further, in the technical scheme, the third step reaction solvent is 2-MeTHF or THF; the reaction temperature is 0 ℃ or lower, preferably-50 ℃ or lower.
In the process of practical experiments, the intermediate B tertiary alcohol is obtained by adding carbonyl in the compound A, and the tertiary alcohol has two configurations of R and S and an original chiral structure in a molecule, so that the molecule belongs to epimers (diastereoisomers) and can be separated theoretically. In the experimental process, when TLC detection is carried out, different developing agents are tried to be adopted, and separation signs cannot be seen all the time; separation by HPLC seems to be evident, but it is always difficult to separate at baseline, and thus separation efficiency is usually very low for this intermediate by preparative chromatography.
Then, the newly produced tertiary alcohol is derivatized, for example, with benzoyl, trityl, triethylsilane, acetyl, p-toluenesulfonyl, benzyl, etc. for protection, and after screening, it is found that when acetyl protection is employed, the tertiary alcohol is completely reacted, and two points of reduced polarity (Rf difference of 0.05 or more) are formed by TLC detection, and the R isomer can be efficiently separated by ordinary silica gel column chromatography, and the target S configuration intermediate D1 can be obtained in high yield.
Further, in the above technical scheme, the synthesis process is typically as follows: the reactor was charged with the compound A synthesized as described in paragraph 0166 and 0178 of patent CN 108602769A. Then dissolving the mixture by toluene, cooling the mixture to below-50 ℃, dropwise adding methyl magnesium chloride Grignard reagent to obtain epimeric tertiary alcohol B, dropwise adding acetic anhydride in the presence of triethylamine, stirring the mixture at room temperature to complete the conversion into acetyl protected tertiary alcohol ester C1, and detecting the ester by TLC as two points with small polarity (developing agent PE/EA is 2/1, Rf is 0.6 and 0.7). Purifying by common silica gel column chromatography to obtain small polar target molecule D1 and slightly larger polar isomer E1. Then DIBAL-H reduces lactone, acetyl is removed at the same time, key intermediate F is obtained in one step, and carboprost 1 is obtained through wittig reaction.
Further, in the above-mentioned technical solution, carboprost 1 is converted into carboprost methyl ester 2 and carboprost amine butanetriol 3 according to the existing literature or patent.
The invention has the positive effects
The invention successfully develops a method for removing the 15R hydroxyl isomer of the carboprost, removes the carboprost 15R hydroxyl isomer in time when the chiral isomer is introduced, avoids the high-efficiency liquid phase separation of the 15R isomer by the final carboprost methyl ester, avoids the two hydroxyl selectivity potential risks and low yield in industrial amplification production caused by using the D-camphorsulfonyl chloride as a resolving agent, separates the carboprost methyl ester by the common silica gel column chromatography, has simple operation, meets the quality requirement of the obtained product, greatly reduces the production cost and improves the comprehensive benefit of the product.
The industrial preparation method of the carboprost { comprising the currently marketed carboprost (1), carboprost methyl ester (2) and carboprost amine butanetriol (3) } has simple operation and high yield, avoids the potential toxic risk of high-activity substances to operators caused by separation at a high-activity stage, improves the product quality, greatly reduces the requirements on production equipment, and improves the product competitiveness.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. The following examples are given for R ═ TBS, TES and Bz. The reagents and starting materials used in the present invention are commercially available.
Example 1 example with protecting agent R ═ TBS
The first step is as follows: 60g of compound A was synthesized as a white solid in a yield of 95% as described in paragraph 0166 and 0178 of CN 108602769A.
The second step is that: in a 2L three-necked flask, compound A (55.0g,145mmol) was added, followed by 800mL of toluene, followed by cooling to-50 ℃ or below under nitrogen, 3M MeMgCl tetrahydrofuran solution (120mL) was added dropwise, and the reaction was stopped when the starting material was completely disappeared by TLC. The reaction mixture was warmed to 0 ℃ and 500mL of a saturated aqueous ammonium chloride solution was slowly added dropwise thereto, followed by addition of a 3M aqueous hydrochloric acid solution dropwise until the pH became 3 to 4. The organic layer was separated, the aqueous layer was extracted with 200mL of ethyl acetate, and the organic layers were combined, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. Filtering, vacuum distilling to obtain crude product, silica gel column flash column chromatography to obtain 55.1g pale yellow viscous liquid B with 96% yield.
In the third step, intermediate B (55g,139mmol) was dissolved in 300mL of dichloromethane under nitrogen, and triethylamine (21.0g,200mmol) was added. Stirring was started, acetic anhydride (18.0g, 176mmol) was added dropwise, and the reaction was stirred at room temperature for 24 hours after the addition. TLC detection, the material disappeared completely, two small polar spots were formed. Concentrating under reduced pressure, washing with half saturated salt water, and drying. The crude product obtained by filtration was subjected to silica gel column chromatography with ethyl acetate/petroleum ether as the mobile phase and subjected to rapid separation to obtain a small-polarity product as a pale yellow oily liquid D1, 36.5g, yield 60%.
The fourth step: to a 500mL reaction flask, compound D1(36.5g,83.2mmol) and 100mL tetrahydrofuran were added, cooled to below-50 ℃ under nitrogen, and a 1.6M DIBAL-H toluene solution (260mL,416mmol) was started dropwise while maintaining the reaction temperature at no more than-50 ℃. After the addition was complete, the reaction was continued for 10 minutes with stirring at this temperature and the starting material was completely lost by TLC to give a slightly more polar product (EA/PE: 1/1, Rf: 0.5). Pouring the reaction solution into a rapidly stirred 1M cold hydrochloric acid aqueous solution, and adding acid while pouring so as to keep the reaction solution in an acidic environment all the time. After the addition, the pH was adjusted to 3-4, the mixture was transferred to a separatory funnel, extracted twice with ethyl acetate, and the organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 36.5g of a pale yellow oily liquid as an intermediate F. The next reaction was carried out without further purification.
The fifth step: under the protection of nitrogen, 4-carboxybutyltriphenylphosphonium bromide (100g,225mmol) and 300mL of tetrahydrofuran were added to a 3L reaction flask with mechanical stirring, the temperature was reduced to-10 deg.C, potassium tert-butoxide (73.0g,0.65mol) was added, and then the mixture was stirred for 10 minutes at-5 deg.C. The temperature was controlled at-5 ℃ to-10 ℃, and a solution of intermediate F (36.5g,0.128mol) in 300mL of tetrahydrofuran was added dropwise to the reaction mixture. After dropping, the reaction was stopped by keeping the temperature for 12 hours. 500mL of water was added to the reaction system. The mixture was extracted with 300mL of ethyl acetate, the pH of the aqueous phase was adjusted to 4 to 5 by adding citric acid, and the mixture was extracted with 300mL of ethyl acetate and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography purification gave 24.5g of a pale yellow viscous oily liquid as casstaglandin 1 with an HPLC purity of 98.1% and a two-step yield of 66.7%.
And a sixth step: carboprost (24.5g,66.8mmol) was dissolved in filtered 135mL isopropanol, tromethamine (8.5g,70.2mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Filtering, concentrating, adding isopropanol and acetone, stirring at 20 deg.C for crystallization, and filtering to obtain wet product 30.0 g. Dissolving the wet product in isopropanol, filtering, removing mechanical impurities, concentrating most of the solvent, adding acetone, crystallizing, filtering, and drying at 40 deg.C to obtain 25.2g white solid. HPLC purity 98.7%, no 15R isomer. The yield thereof was found to be 77.0%.
Example 2 example with protecting agent R ═ TES
The first step is as follows: 6.0g of Compound A was synthesized as a white solid in a yield of 95% as described in paragraph 0166 and 0178 of CN 108602769A.
The second step is that: in a 2L three-necked flask, compound A (5.5g,14.5mmol) was added, followed by addition of 80mL of toluene, followed by cooling to-50 ℃ or below under nitrogen, 3M MeMgCl tetrahydrofuran solution (12mL) was added dropwise, and the reaction was stopped when the starting material was completely disappeared by TLC detection. The reaction mixture was warmed to 0 ℃ and 50mL of a saturated aqueous ammonium chloride solution was slowly added dropwise thereto, followed by addition of a 3M aqueous hydrochloric acid solution dropwise until the pH became 3 to 4. The organic layer was separated, the aqueous layer was extracted with 20mL of ethyl acetate, and the organic layers were combined, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. Filtering, vacuum distilling to obtain crude product, silica gel column flash column chromatography to obtain 5.5g pale yellow viscous liquid B with 96% yield.
In the third step, intermediate B (5.5g,13.9mmol) was dissolved in 30mL of dichloromethane under nitrogen, and triethylamine (2.1g,20mmol) was added. Stirring was started, acetic anhydride (1.8g, 17.6mmol) was added dropwise, and the reaction was stirred at room temperature for 24 hours after the addition was completed. TLC detection, the material disappeared completely, two small polar spots were formed. Concentrating under reduced pressure, washing with half saturated salt water, and drying. The crude product obtained by filtration was subjected to silica gel column chromatography with ethyl acetate/petroleum ether as the mobile phase and subjected to rapid separation to obtain a small-polarity product as a pale yellow oily liquid D1, 3.60g, yield 59%.
The fourth step: to a 100mL reaction flask, compound D1(3.6g,8.2mmol) and 10mL tetrahydrofuran were added, cooled to below-50 ℃ under nitrogen, and 1.6M DIBAL-H in toluene (25.6mL,41.0mmol) was added dropwise while maintaining the reaction temperature at no more than-50 ℃. After the addition was complete, the reaction was continued at this temperature for 10 minutes with complete disappearance of starting material by TLC, yielding a slightly more polar product. Pouring the reaction solution into a rapidly stirred 1M cold hydrochloric acid aqueous solution, and adding acid while pouring so as to keep the reaction solution in an acidic environment all the time. After the addition, the pH was adjusted to 3-4, the mixture was transferred to a separatory funnel, extracted twice with ethyl acetate, and the organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 3.70g of a pale yellow oily liquid as an intermediate F. The next reaction was carried out without further purification.
The fifth step: under the protection of nitrogen, in a 300mL reaction bottle with a mechanical stirrer, 4-carboxybutyltriphenylphosphonium bromide (10g,22.5mmol) and 30mL tetrahydrofuran were added, the temperature was reduced to-10 ℃, potassium tert-butoxide (7.30g,65mmol) was added, and then the mixture was stirred for 10 minutes at-5 ℃. The temperature was controlled at-5 ℃ to-10 ℃, and a solution of intermediate F (3.70g,13.0mmol) in 30mL of tetrahydrofuran was added dropwise to the reaction mixture. After dropping, the reaction was stopped by keeping the temperature for 12 hours. 50mL of water was added to the reaction system. The mixture was extracted with 30mL of ethyl acetate, the pH of the aqueous phase was adjusted to 4 to 5 by adding citric acid, and the mixture was extracted with 30mL of ethyl acetate and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography purification gave 2.45g of a pale yellow viscous oily liquid as caprostaglandin 1 with an HPLC purity of 98.3% and a two-step yield of 66.8%.
And a sixth step: carboprost (2.45g,6.65mmol) was dissolved in filtered 13.5mL isopropanol, 0.85g tromethamine (7.02mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Filtering, concentrating, adding isopropanol and acetone, stirring at 20 deg.C for crystallization, and filtering to obtain wet product 3.0 g. Dissolving the wet product in isopropanol, filtering, removing mechanical impurities, concentrating most of the solvent, adding acetone, crystallizing, filtering, and drying at 40 deg.C to obtain 2.5g white solid. HPLC purity 98.8%, no 15R isomer. The yield thereof was found to be 77.0%.
Example 3 is exemplified with the protecting agent R ═ Bz
The first step is as follows: 30g of compound A was synthesized as an oily liquid in a yield of 80% as described in paragraph 0166 and 0178 of CN 108602769A.
The second step is that: in a 1L three-necked flask, compound A (25.0g) was added, followed by addition of 400mL of toluene, followed by cooling to-50 ℃ or below under nitrogen, and 3M MeMgCl tetrahydrofuran solution (60mL) was added dropwise to complete disappearance of the starting materials by TLC detection, thereby stopping the reaction. The reaction mixture was warmed to 0 ℃ and 250mL of a saturated aqueous ammonium chloride solution was slowly added dropwise thereto, followed by addition of a 3M aqueous hydrochloric acid solution dropwise until the pH became 3 to 4. The organic layer was separated, the aqueous layer was extracted with 100mL of ethyl acetate, and the organic layers were combined, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. Filtering, vacuum distilling to obtain crude product, silica gel column flash column chromatography to obtain 27.5g pale yellow viscous liquid B, yield 96%.
In the third step, intermediate B (27.5g) was dissolved in 150mL of dichloromethane under nitrogen and triethylamine (10.5g) was added. Stirring was started, acetic anhydride (9.0g) was added dropwise thereto, and the reaction was stirred at room temperature for 24 hours after the completion of the addition. TLC detection, the material disappeared completely, two small polar spots were formed. Concentrating under reduced pressure, washing with half saturated salt water, and drying. The crude product obtained by filtration was subjected to silica gel column chromatography with ethyl acetate/petroleum ether as the mobile phase and subjected to rapid separation to obtain a small-polarity product as a pale yellow oily liquid D1, 18.2g, yield 59%.
The fourth step: to a 250mL reaction flask, compound D1(18.2g,42.5mmol) and 50mL tetrahydrofuran were added, cooled to below-50 ℃ under nitrogen, and 1.6M DIBAL-H in toluene (187.5mL,300.0mmol) was added dropwise while maintaining the reaction temperature at no more than-50 ℃. After the addition was complete, the reaction was continued at this temperature for 10 minutes with complete disappearance of starting material by TLC, yielding a slightly more polar product. Pouring the reaction solution into a rapidly stirred 1M cold hydrochloric acid aqueous solution, and adding acid while pouring so as to keep the reaction solution in an acidic environment all the time. After the addition, the pH was adjusted to 3-4, the mixture was transferred to a separatory funnel, extracted twice with ethyl acetate, and the organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 18.0g of a pale yellow oily liquid as an intermediate F. The next reaction was carried out without further purification.
The fifth step: under the protection of nitrogen, 4-carboxybutyltriphenylphosphonium bromide (50g) and 150mL of tetrahydrofuran were added to a 3L reaction flask with mechanical stirring, the temperature was reduced to-10 ℃, potassium tert-butoxide (36.5g) was added, and then the mixture was stirred for 10 minutes at-5 ℃. The temperature was controlled at-5 ℃ to-10 ℃, and a solution of intermediate F (18.0g,63.4mmol) in 150mL of tetrahydrofuran was added dropwise to the reaction mixture. After dropping, the reaction was stopped by keeping the temperature for 12 hours. 150mL of water was added to the reaction system. The mixture was extracted with 150mL of ethyl acetate, the pH of the aqueous phase was adjusted to 4 to 5 by adding citric acid, and the mixture was extracted with 150mL of ethyl acetate and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography purification gave 12.2g of a pale yellow viscous oily liquid as casstaglandin 1, with an HPLC purity of 98.0% and a two-step yield of 66.5%.
And a sixth step: carboprost (12.2g,33.1mmol) was dissolved in filtered 70mL isopropanol, tromethamine (4.2g,34.7mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Filtering, concentrating, adding isopropanol and acetone, stirring at 20 deg.C for crystallization, and filtering to obtain wet product 15.0 g. Dissolving the wet product in isopropanol, filtering, removing mechanical impurities, concentrating most of the solvent, adding acetone, crystallizing, filtering, and drying at 40 deg.C to obtain 12.5g white solid. HPLC purity 98.5% without 15R isomer. The yield thereof was found to be 76.5%.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (10)
1. A method for separating the 15 th isomer of carboprost, comprising the steps of: and (3) performing PG protection on the compound B with 15-site hydroxyl tertiary alcohol to obtain 15-site S-type carboprost D and 15-site R-type carboprost E (forming a 15-site hydroxyl tertiary alcohol compound C), and separating to obtain a 15-site S-type carboprost D pure product and a 15-site R-type carboprost E pure product. The corresponding structure is as follows:
2. The method of separating carboprost 15 isomer of claim 1, wherein: the PG protection is selected from benzoyl, trityl, triethyl silicon, acetyl, p-toluenesulfonyl or benzyl.
3. The method of separating carboprost 15 isomer of claim 1, wherein: the difference value of the separation Rf is more than 0.05, and column chromatography, a thin-layer color plate or an HPLC preparative column is adopted for separation.
4. A preparation method of carboprost 1 is characterized in that the reaction equation is represented as follows:
wherein, R is THP, TES, TBS or Bz;
the method comprises the following steps: carrying out addition reaction on the compound A and a methyl Grignard reagent at low temperature to obtain a compound B; protecting the compound B with acetyl to obtain a compound C1; separating the compound C1 by column chromatography to obtain 15S carboprost D1; 15S carboprost D1 to obtain compound F; the compound F is subjected to a Witig reaction to obtain carboprost 1.
5. The method of claim 4, wherein the carboprost 1 is prepared by: the first step methyl grignard reagent is selected from methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
6. The method of claim 4, wherein the carboprost 1 is prepared by: the first step reaction solvent is one or more of THF, 2-MeTHF or toluene; the reaction temperature is below 0 ℃.
7. The method of claim 4, wherein the carboprost 1 is prepared by: the second acetyl protection is carried out by using acetyl chloride or acetic anhydride under the condition of triethylamine, pyridine or diisopropylethylamine.
8. The method of claim 4, wherein the carboprost 1 is prepared by: and in the third step, DIBAL-H is adopted for reduction, and acetyl is also removed at the same time without additional hydrolysis.
9. The method of claim 4, wherein the carboprost 1 is prepared by: the third step reaction solvent is 2-MeTHF or THF; the reaction temperature is below 0 ℃.
10. A preparation method of carboprost methyl ester 2 and carboprost tromethamine 3 is characterized in that: carboprost 1 is synthesized by the method of any of claims 4-8, and then carboprost 1 is converted to carboprost methyl ester 2 and carboprost tromethamine 3 according to the literature or patent.
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| CN113548993B (en) * | 2021-09-01 | 2022-05-27 | 河北化工医药职业技术学院 | Preparation method of carboprost |
| CN115160202A (en) * | 2022-07-30 | 2022-10-11 | 广州楷石医药有限公司 | Preparation method of carboprost tromethamine and intermediate thereof |
| CN115160202B (en) * | 2022-07-30 | 2023-10-31 | 广州楷石医药有限公司 | Preparation method of carboprost tromethamine and intermediate thereof |
| CN115819307A (en) * | 2022-12-21 | 2023-03-21 | 上海彩迩文生化科技有限公司 | Preparation method of prostaglandin E1 |
| CN115819307B (en) * | 2022-12-21 | 2024-03-12 | 上海彩迩文生化科技有限公司 | Preparation method of prostaglandin E1 |
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