CN109400513A - A kind of purification process of Carboprost - Google Patents
A kind of purification process of Carboprost Download PDFInfo
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- CN109400513A CN109400513A CN201811419603.XA CN201811419603A CN109400513A CN 109400513 A CN109400513 A CN 109400513A CN 201811419603 A CN201811419603 A CN 201811419603A CN 109400513 A CN109400513 A CN 109400513A
- Authority
- CN
- China
- Prior art keywords
- carboprost
- solvent
- crude product
- carboxylate
- dosage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960003395 carboprost Drugs 0.000 title claims abstract description 86
- 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 68
- 238000000746 purification Methods 0.000 title claims abstract description 12
- -1 benzyl halogen compound Chemical class 0.000 claims abstract description 43
- 239000012043 crude product Substances 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000926 separation method Methods 0.000 claims abstract description 19
- 239000000047 product Substances 0.000 claims abstract description 8
- 230000032050 esterification Effects 0.000 claims abstract description 7
- 238000005886 esterification reaction Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims description 31
- 239000007788 liquid Substances 0.000 claims description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000010792 warming Methods 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims 3
- 150000007942 carboxylates Chemical class 0.000 claims 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 6
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000001681 protective effect Effects 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 238000003883 substance clean up Methods 0.000 abstract description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract 3
- 229960004217 benzyl alcohol Drugs 0.000 abstract 1
- 235000019445 benzyl alcohol Nutrition 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 150000003180 prostaglandins Chemical class 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 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 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 2
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-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
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000005578 Rivina humilis Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- XUHFBOUSHUEAQZ-UHFFFAOYSA-N bromobenzyl cyanide Chemical compound N#CC(Br)C1=CC=CC=C1 XUHFBOUSHUEAQZ-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229960001342 dinoprost Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- PXGPLTODNUVGFL-YNNPMVKQSA-N prostaglandin F2alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-YNNPMVKQSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 210000004291 uterus Anatomy 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
- 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
Abstract
The invention belongs to compound purification arts, and in particular to a kind of purification process of Carboprost.The present invention is using crude product Carboprost as starting material, and by the way that esterification occurs with benzyl halogen compound, crystallization is split, and the Carboprost of single configuration high-purity is prepared in hydrolysis removing benzylalcohol.The technological reaction and post-processing operation are simple, and being not required to column chromatography for separation diastereoisomer can be obtained high quality of products.The invented technology is environmentally protective, economical and practical, is extremely suitable for industrial production.
Description
Technical field
The present invention relates to compound purification arts, and in particular to a kind of purification process of Carboprost.
Background technique
Prostaglandin (prostaglandins, PGs) is a kind of unsaturated fatty acid by being present in animal and human body
The active material with a variety of physiological actions of composition.Prostaglandin (PGs) is generated by arachidonic acid oxidation metabolic in vivo,
Structure is a five rings and the 20 carbon unsaturated fatty acids that two side chains are constituted.The effect of prostaglandin is extremely wide and complicated,
Different types of prostaglandin can produce entirely different effect to different cells, such as PGE can expand blood vessel, increase organ
Blood flow reduces peripheral resistance, and has row's sodium effect, so that blood pressure be made to decline；And PGF effect is more complicated, can make rabbit, cat
Blood pressure decline, but make rat, dog blood pressure increase etc..
Carboprost is romethamine key intermediate, and romethamine is containing prostaglandin F2
The tromethamine salting liquid of (15S) -15 methyl-derivatives of α, wherein the ratio of Carboprost and tromethamine is 1:1.
The miscarriage that it is 13 weeks to 20 weeks the gestational period that romethamine, which is suitable for, there is by force Uterus during Pregnancy smooth muscle
Strong contraction, can obviously increase cell bio-activity level, and mechanism of action is dense by increasing intracellular calcium
Degree inhibits adenyl cyclase, directly stimulates gap to link the mechanism such as to form and increase uterine leio Muscle tensility, and then cause myogen
The contraction of fiber enhances uterine contraction, to realize the purpose of hemostasis.
The synthetic strategy of Carboprost is that two sides are respectively connected at α and ω using lactone A in key intermediate section
Chain, as noted above, this is also the industrial main method of current romethamine.1974, Upjohn company
(15S) -15 methyl-derivatives of (J.Am.Chem.Soc., 1974,96,5865) synthesis of prostaglandins F2 α for the first time, patent
WO2008081191 reports similar synthetic method: major impurity is 15- chiral isomer impurity 1 in crude product Carboprost H
With 5,6- transisomer impurity 2, in the isomer separation of crude product Carboprost H, they are all made of column chromatography for separation, column
Chromatography technological operation is cumbersome, and production capacity is low, high production cost.
With before the Chromatorex MB type silica gel success column chromatography for separation card of partial size 40-70um in WO2017093770A1
Plain methyl esters H is arranged, yield reaches 57%, and impurity is no more than 0.5%, but the chirality padding price of the method is costly, and uses
Highly toxic Methylsulfate or potassium iodide carry out esterification, are not suitable for industrialized production.Patent CN1136938C is disclosed
Carboprost methylate H is separated using Simulated Moving Bed Chromatography (abbreviation SMBC) separation system, but this method to the investment of equipment compared with
Height is not suitable for industrialized production, and separation purity only reaches 90%.
Currently, the Carboprost of high-purity is obtained generally by the column chromatography for separation of carboprost methylate, but before blocking
The column plain methyl esters column chromatography for separation isomer impurities period is long, low output, and solvent usage amount is big, causes its application prospect by office
Limit, and Carboprost carboxylate Crystallization Separation is seldom reported both at home and abroad, the present invention provides it is a kind of it is new be suitable for industrialized production,
Environmentally protective, economical and practical purification process.
Summary of the invention
Applicants have found that being modified with benzyl halogen crude product Carboprost, the esterification obtained under alkaline condition is produced
Object, then crude product is recrystallized, 15- (S)-Carboprost esterification products can be obtained；Then hydrolysis can be obtained under alkaline condition again
The Carboprost of single configuration.The process conditions are mild, and overcome needs the specific silica gel column chromatography bring period in the prior art
It is long, low output, and the problem that solvent usage amount is big, while the technique is environmentally protective, and it is economical and practical, it is very suitable for industrial metaplasia
It produces.
The purification process response path of Carboprost of the present invention is as follows:
Specific purification process is as follows:
(1) Carboprost crude product reacts to obtain Carboprost esterification products with benzyl halogen compound:
Carboprost crude product, solvent A, benzyl halogen compound and alkali are added in the reaction vessel, reaction solution is warming up to 20-60
DEG C, (TLC detects raw material Carboprost and disappears) until the reaction is complete is stirred to react at 20-60 DEG C, to reacting liquid temperature to room
Wen Hou, filtering, filtrate decompression are concentrated to get Carboprost carboxylate crude product；
(2) chiral resolution of Carboprost carboxylate:
The Carboprost carboxylate crude product that step (1) is obtained is added in recrystallisation solvent B, and reaction solution is warming up to 30-80
DEG C, 2-6h is stirred at 30-80 DEG C, then after reaction solution natural cooling, is filtered, washed, is dried to obtain Carboprost esterification
Object；
(3) Carboprost carboxylate hydrolyzes obtain Carboprost under alkaline condition:
Carboprost carboxylate, solvent C and aqueous slkali that step (2) obtain are added in the reaction vessel, stirs at room temperature
Reaction (TLC detects Carboprost carboxylate and disappears) until the reaction is complete is mixed, is then concentrated under reduced pressure and removes solvent C, be then added
Solvent D and water carry out extraction liquid separation, separate water layer；The pH of water layer is adjusted to 3-4, liquid separation with hydrochloric acid, gained water phase is extracted with solvent D
After taking and (preferably extracting at least twice), gained organic phase is dried, filtered with anhydrous sodium sulfate, before filtrate decompression is concentrated to give liquid card
Column element；
The molar ratio of benzyl halogen compound, alkali and Carboprost crude product dosage is (1-5): (1-5) in the step (1): 1,
Preferably (1-1.5): (1-1.5): 1.
Further, the structural formula of benzyl halogen compound described in step (1) isWherein X be selected from fluorine, chlorine, bromine and
Any one in iodine, R2Any one in methoxyl group, methyl, hydrogen, chlorine, bromine, nitro and cyano, R2In methylene
Ortho position, meta or para position.
Further, the benzyl halogen compound is p-methoxybenzyl chloride or 3- cyano-benzyl bromide.
Further, solvent A described in step (1) is selected from tetrahydrofuran, acetone, dimethyl sulfoxide, N, N- dimethyl formyl
One or more of amine and acetonitrile, the solvent A dosage and Carboprost crude product amount ratio are (10-50) mL:1g.
Further, the solvent A is tetrahydrofuran or acetone.
Further, alkali described in step (1) is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate
Or cesium carbonate.
Further, the time being stirred to react in the step (1) is 1-3 hours.
Further, recrystallisation solvent B described in step (2) is isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, methyl
One or more of tertbutyl ether, ethyl acetate, acetonitrile and acetone, the amount ratio of dosage and Carboprost carboxylate crude product
For (5-30) mL:1g, preferably (5-10) mL:1g.
Further, the recrystallisation solvent B is the methyl tertiary butyl ether(MTBE) and acetone mixed solvent of volume ratio 17:1, or
The recrystallisation solvent B is isopropyl ether.
Further, solvent C described in step (3) is isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, methyl- tert fourth
One or more of base ether, ethyl acetate, methylene chloride, anhydrous methanol and dehydrated alcohol, dosage and Carboprost are esterified
The amount ratio of object is (2-30) mL:1g, preferably (2-6) mL:1g.
Further, the solvent C is tetrahydrofuran or anhydrous methanol.
Further, aqueous slkali described in step (3) be potassium hydroxide solution, sodium hydroxide solution, lithium hydroxide solution,
One of sodium carbonate liquor, solution of potassium carbonate and cesium carbonate solution, the preferably sodium hydroxide solution of 2wt%.
Further, the molar ratio of the dosage and Carboprost carboxylate dosage of alkali is in aqueous slkali described in step (3)
(1-10): 1, preferably (3-6): 1.
Further, the time being stirred to react in the step (3) is 0.5~6 hour, preferably 1-3 hours.
Further, solvent D described in step (3) is isopropyl ether, 2- methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), 2- fourth
One or more of alcohol, n-butanol, ethyl acetate and methylene chloride, preferably methyl tertiary butyl ether(MTBE) and/or ethyl acetate.
Further, the purity of Carboprost crude product described in step (1) is not less than 45%.
Compared with prior art, the invention has the following advantages that
1. derivative reagent used in method provided by the invention is simple and easy to get, used crystallisation step has condition temperature
With it is easy to operate the features such as.
2. the present invention provides a kind of preparation methods of high-purity Carboprost, especially chiral to its major impurity 15-
The purifies and separates of isomers and 5,6- transisomers.Carboprost HPLC purity after purification is at least 99.5%, and list is miscellaneous
Content is no more than 0.2%.
3. method cost of material of the invention is cheap, input cost is low, is suitable for industrialized production.
Detailed description of the invention
Fig. 1 is the HPLC purity spectrogram for the liquid Carboprost that 2 step 3 of embodiment obtains.
Specific embodiment
The technical schemes of the invention are described in detail combined with specific embodiments below, it should be noted that implementation described below
Example is exemplary, and for explaining only the invention, and is not considered as limiting the invention.In addition, if without specifically
It is bright, in the following embodiments used by all raw materials be market be commercially available, or be referred to document or
The method synthesis known, be also what those skilled in the art were easy to get for the reaction condition that do not list.
(page 9 of raw material Carboprost crude product method according to disclosed in WO2008081191A1 used in following embodiment
Paragraph 1 is to the 3rd section of page 11) it is prepared.
Described impurity 1 is 15- chiral isomer in the present invention, and impurity 2 is 5,6- transisomers, and structural formula is as follows:
Embodiment 1: a kind of purification process of Carboprost, steps are as follows:
Step 1:
Equipped with thermometer tri- mouthfuls of reaction flasks of 500ml in be added liquid crude product Carboprost (15.0g, 0.0407mol,
HPLC detects its Carboprost content: 54.66%, wherein the integral of Carboprost and 15- chiral isomer (impurity 1), which compares, is
61:39), tetrahydrofuran (300ml) then is injected thereto, then K is added thereto2CO3(6.6g, 0.048mol) and to methoxy
Reaction solution is warming up to 50 DEG C by base benzyl chloride (7.6g, 0.048mol), and 2 hours are stirred at 50 DEG C, and (TLC detects raw material card forefront
Element disappears), it is cooled to room temperature (25 DEG C, similarly hereinafter), filters to reaction solution, filtrate decompression is concentrated to give the sticky shape crude product of 20.3g yellow
Carboprost is to methoxybenzyl ester.
Step 2:
To whole crude product Carboprosts obtained above to addition methyl tertiary butyl ether(MTBE) (170mL) and acetone in methoxybenzyl ester
(10mL) is warming up to 55 DEG C, stirs 2 hours at 55 DEG C, is naturally cooling to room temperature, filtering, by the white solid first of precipitation
Base tertbutyl ether (15mL) washs, and the vacuum drying 4h at 60 DEG C of the solid after washing obtains the Carboprost of 10.3g white to first
Oxygen benzyl ester solid.
Step 3:
In tri- mouthfuls of reaction flasks of 500ml equipped with thermometer, it is solid to methoxybenzyl ester that the Carboprost that step 2 obtains is added
The sodium hydrate aqueous solution (210mL, 0.105mol) of body (10.3g, 0.021mol), tetrahydrofuran (50mL) and 2wt%, in room
The lower stirring of temperature 1 hour (TLC detects raw material Carboprost and disappears to methoxybenzyl ester)；It is concentrated under reduced pressure after removing solvents tetrahydrofurane,
Methyl tertiary butyl ether(MTBE) (50ml) is added thereto and water (50ml) carries out extraction liquid separation, separates water layer；It is added in gained water layer
Dilute HCl solution (1wt%, 370ml) adjusts pH to 3-4, liquid separation, and gained water phase is extracted twice with methyl tertiary butyl ether(MTBE), each first
Base tertbutyl ether dosage 80mL merges organic phase extracted twice, is dried, filtered with anhydrous sodium sulfate (1.0g), filters product liquid
7.6g colourless oil liquid Carboprost is concentrated under reduced pressure to obtain.
The total recovery of three steps of the present embodiment is the purity of 92.7%, HPLC detecting step, three Product liquid Carboprost
Reach 99.79%, 1 content of impurity is 0.13%, and 2 content of impurity is 0.08%.
Embodiment 2: a kind of purification process of Carboprost, steps are as follows:
Step 1:
Equipped with thermometer tri- mouthfuls of reaction flasks of 2000ml in be added liquid crude product Carboprost (50.0g, 0.136mol,
HPLC detects its Carboprost content: 60.96%, wherein the integral of Carboprost and 15- chiral isomer (impurity 1), which compares, is
63:37), tetrahydrofuran (1000ml) then is injected thereto, then sodium hydroxide (6.0g, 0.150mol) and 3- is added thereto
Cyano-benzyl bromide (29.3g, 0.150mol) is stirred at room temperature 1 hour (TLC detects raw material Carboprost and disappears), filters, filter
The sticky shape crude product Carboprost -3- cyano benzyl ester of 65.0g yellow is concentrated under reduced pressure to obtain in liquid.
Step 2:
Methyl tertiary butyl ether(MTBE) (510mL) and acetone is added into whole crude product Carboprost 3- cyano benzyl esters obtained above
(30mL) is warming up to 55 DEG C, stirs 4 hours at 55 DEG C, is naturally cooling to room temperature, filtering, by the white solid first of precipitation
Base tertbutyl ether (50mL) washs, and the vacuum drying 6h at 60 DEG C of the solid after washing obtains the Carboprost -3- of 36.5g white
Cyano benzyl ester solid.
Step 3:
In tri- mouthfuls of reaction flasks of 500ml equipped with thermometer, it is solid that the Carboprost -3- cyano benzyl ester that step 2 obtains is added
The sodium hydrate aqueous solution (750mL, 0.377mol) of body (36.5g, 0.075mol), tetrahydrofuran (200mL) and 2wt%,
It stirs at room temperature 1 hour (TLC detects raw material Carboprost -3- cyano benzyl ester and disappears)；It is concentrated under reduced pressure and removes solvents tetrahydrofurane
Afterwards, ethyl acetate (200ml) is added thereto and water (200ml) carries out extraction liquid separation, separate water layer；It is added in gained water layer
Dilute HCl solution (1wt%, 1460ml) adjusts pH to 3-4, liquid separation, and gained water phase is extracted with ethyl acetate twice, each acetic acid second
Ester dosage 320mL merges organic phase extracted twice, is dried, filtered with anhydrous sodium sulfate (5.0g), filtrate decompression is concentrated to give
27.4g colourless oil liquid Carboprost.
The total recovery of three steps of the present embodiment is the purity of 89.9%, HPLC detecting step, three Product liquid Carboprost
Reach 99.82%, 1 content of impurity is 0.08%, and 2 content of impurity is 0.10%.
The HPLC purity spectrogram for the liquid Carboprost that the present embodiment step 3 obtains, as shown in Figure 1, data are such as in map
The following table 1.
Table 1
Note: being blank peak at retention time 49.2min.
Embodiment 3: a kind of purification process of Carboprost, steps are as follows:
Step 1:
Equipped with thermometer tri- mouthfuls of reaction flasks of 500ml in be added liquid crude product Carboprost (15.0g, 0.0407mol,
HPLC detects its Carboprost content: 49.60%, wherein the integral of Carboprost and 15- chiral isomer (impurity 1), which compares, is
55:45), acetone (300ml) then is injected thereto, then K is added thereto2CO3(6.6g, 0.048mol) and to methoxybenzyl
Reaction solution is warming up to 50 DEG C by chlorine (7.6g, 0.048mol), and 2 hours are stirred at 50 DEG C, and (TLC detection raw material Carboprost disappears
Lose), it is cooled to room temperature, filters to reaction solution, filtrate decompression is concentrated to give the sticky shape crude product card forefront of 20.5g yellow to methoxy benzyl
Ester.
Step 2:
Isopropyl ether (170mL) is added in methoxybenzyl ester to whole crude product card forefront obtained above, is warming up to 65 DEG C,
It is stirred 2 hours at 65 DEG C, is naturally cooling to room temperature, filtered, the white solid of precipitation is washed with isopropyl ether (15mL), after washing
Solid at 60 DEG C vacuum drying 4h, obtain the card forefront of 8.7g white to methoxybenzyl ester solid.
Step 3:
In tri- mouthfuls of reaction flasks of 500ml equipped with thermometer, the card forefront that addition step 2 obtains is to methoxybenzyl ester solid
The sodium hydrate aqueous solution (180mL, 0.089mol) of (8.7g, 0.018mol), anhydrous methanol (50mL) and 2wt%, in room temperature
Lower stirring 1 hour (TLC detects raw material Carboprost and disappears to methoxybenzyl ester)；It is concentrated under reduced pressure after removing solvent methanol, thereto
Methyl tertiary butyl ether(MTBE) (50ml) is added and water (50ml) carries out extraction liquid separation, separates water layer；It is molten that dilute HCl is added in gained water layer
Liquid (1wt%, 350ml) adjusts pH to 3-4, liquid separation, and gained water phase is extracted twice with methyl tertiary butyl ether(MTBE), each methyl tertbutyl
Ether dosage 80mL merges organic phase extracted twice, is dried, filtered with anhydrous sodium sulfate (1.0g), filtrate decompression is concentrated to give
6.5g colourless oil liquid Carboprost.
The total recovery of three steps of the present embodiment is that 87.3%, HPLC detecting step, three Product liquid Carboprost purity reaches
To 99.76%, 1 content of impurity is 0.14%, and 2 content of impurity is 0.10%.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is with example
Property, it is not considered as limiting the invention, those skilled in the art are not departing from the principle of the present invention and objective
In the case where the above embodiments can be changed, modify, replacement and variant within the scope of the invention.
Claims (9)
1. a kind of purification process of Carboprost, includes the following steps:
(1) Carboprost crude product reacts to obtain Carboprost esterification products with benzyl halogen compound:
Carboprost crude product, solvent A, benzyl halogen compound and alkali are added in the reaction vessel, reaction solution is warming up to 20-60 DEG C,
It is stirred to react at 20-60 DEG C until the reaction is complete, after reacting liquid temperature to room temperature, filtering, filtrate decompression is concentrated to get card
Forefront element carboxylate crude product；
(2) chiral resolution of Carboprost carboxylate:
The Carboprost carboxylate crude product that step (1) is obtained is added in recrystallisation solvent B, and reaction solution is warming up to 30-80 DEG C,
2-6h is stirred at 30-80 DEG C, then after reaction solution natural cooling, is filtered, washed, is dried to obtain Carboprost carboxylate；
(3) Carboprost carboxylate hydrolyzes obtain Carboprost under alkaline condition:
Carboprost carboxylate, solvent C and aqueous slkali that step (2) obtain are added in the reaction vessel, is stirred at room temperature anti-
It then should be concentrated under reduced pressure until the reaction is complete and remove solvent C, solvent D then is added and water carries out extraction liquid separation, separates water layer；
The pH of water layer is adjusted to 3-4 with hydrochloric acid, liquid separation, after gained water phase is extracted with solvent D, gained organic phase is dry with anhydrous sodium sulfate
Dry, filtering, filtrate decompression is concentrated to give liquid Carboprost；
The molar ratio of benzyl halogen compound, alkali and Carboprost crude product dosage is (1-5): (1-5): 1 in the step (1).
2. the method according to claim 1, wherein the structural formula of benzyl halogen compound described in step (1) is, wherein any one of X in fluorine, chlorine, bromine and iodine, R2Selected from methoxyl group, methyl, hydrogen, chlorine, bromine, nitro and cyanogen
Any one in base, R2Ortho position, meta or para position in methylene.
3. according to the method described in claim 2, it is characterized in that, solvent A described in step (1) be selected from tetrahydrofuran, acetone,
Dimethyl sulfoxide,N,NOne or more of dimethylformamide and acetonitrile, the solvent A dosage and Carboprost crude product dosage
Than for (10-50) mL:1g.
4. according to the method described in claim 3, it is characterized in that, alkali described in step (1) is selected from potassium hydroxide, hydroxide
Sodium, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.
5. according to the method described in claim 4, it is characterized in that, recrystallisation solvent B described in step (2) is isopropyl ether, tetrahydro
One or more of furans, 2- methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate, acetonitrile and acetone, dosage and card
The amount ratio of forefront element carboxylate crude product is (5-30) mL:1g.
6. according to the method described in claim 5, it is characterized in that, solvent C described in step (3) be isopropyl ether, tetrahydrofuran,
One of 2- methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate, methylene chloride, anhydrous methanol and dehydrated alcohol are several
Kind, the amount ratio of dosage and Carboprost carboxylate is (2-30) mL:1g.
7. according to the method described in claim 6, it is characterized in that, aqueous slkali described in step (3) is potassium hydroxide solution, hydrogen
One of sodium hydroxide solution, lithium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate and cesium carbonate solution, the aqueous slkali
The dosage of middle alkali and the molar ratio of Carboprost carboxylate dosage are (1-10): 1.
8. the method according to the description of claim 7 is characterized in that solvent D described in step (3) is isopropyl ether, 2- methyl four
One or more of hydrogen furans, methyl tertiary butyl ether(MTBE), 2- butanol, n-butanol, ethyl acetate and methylene chloride.
9. method according to claim 1-8, which is characterized in that Carboprost crude product described in step (1)
Purity is not less than 45%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110746333A (en) * | 2019-10-31 | 2020-02-04 | 武汉嘉诺康医药技术有限公司 | Method for separating carboprost isomer |
| CN113548993A (en) * | 2021-09-01 | 2021-10-26 | 河北化工医药职业技术学院 | Preparation method of carboprost |
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| GB1362956A (en) * | 1970-11-10 | 1974-08-07 | Ono Pharmaceutical Co | Prostaglandin esters and production thereof |
| USB315363I5 (en) * | 1970-11-27 | 1975-01-28 | Upjohn Co | |
| US3890372A (en) * | 1974-01-08 | 1975-06-17 | Upjohn Co | Amino substituted phenyl and naphthyl esters of PGF{HD 2{301 {B - type compounds |
| CN102816099A (en) * | 2011-06-09 | 2012-12-12 | 上海天伟生物制药有限公司 | High-purity carboprost tromethamine, and preparation method and application thereof |
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2018
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| GB1362956A (en) * | 1970-11-10 | 1974-08-07 | Ono Pharmaceutical Co | Prostaglandin esters and production thereof |
| USB315363I5 (en) * | 1970-11-27 | 1975-01-28 | Upjohn Co | |
| US3890372A (en) * | 1974-01-08 | 1975-06-17 | Upjohn Co | Amino substituted phenyl and naphthyl esters of PGF{HD 2{301 {B - type compounds |
| CN102816099A (en) * | 2011-06-09 | 2012-12-12 | 上海天伟生物制药有限公司 | High-purity carboprost tromethamine, and preparation method and application thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110746333A (en) * | 2019-10-31 | 2020-02-04 | 武汉嘉诺康医药技术有限公司 | Method for separating carboprost isomer |
| CN110746333B (en) * | 2019-10-31 | 2021-06-04 | 武汉嘉诺康医药技术有限公司 | Method for separating carboprost isomer |
| CN113548993A (en) * | 2021-09-01 | 2021-10-26 | 河北化工医药职业技术学院 | Preparation method of carboprost |
| CN113548993B (en) * | 2021-09-01 | 2022-05-27 | 河北化工医药职业技术学院 | Preparation method of carboprost |
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