CN106565771A - Phosphorylcholine compound Lys-PC containing propyl dimethicone and preparation method thereof - Google Patents
Phosphorylcholine compound Lys-PC containing propyl dimethicone and preparation method thereof Download PDFInfo
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- CN106565771A CN106565771A CN201610988842.1A CN201610988842A CN106565771A CN 106565771 A CN106565771 A CN 106565771A CN 201610988842 A CN201610988842 A CN 201610988842A CN 106565771 A CN106565771 A CN 106565771A
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- Prior art keywords
- compound
- phosphorylcholine
- containing double
- double amino
- amino
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- 229950004354 phosphorylcholine Drugs 0.000 title claims abstract description 27
- -1 Phosphorylcholine compound Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 229940008099 dimethicone Drugs 0.000 title abstract 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 title abstract 2
- 239000004205 dimethyl polysiloxane Substances 0.000 title abstract 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 title abstract 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 title abstract 2
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 8
- 239000004970 Chain extender Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000002537 cosmetic Substances 0.000 claims abstract description 3
- 238000001415 gene therapy Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 11
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 10
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 claims description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 230000003750 conditioning effect Effects 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000012467 final product Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- VJRYWXNPDKUNNG-UHFFFAOYSA-N 1,3,2lambda5-dioxaphospholane 2-oxide Chemical compound O=P1OCCO1 VJRYWXNPDKUNNG-UHFFFAOYSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 4
- 239000004472 Lysine Substances 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 3
- 210000000232 gallbladder Anatomy 0.000 claims description 3
- 238000007142 ring opening reaction Methods 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 18
- 230000004048 modification Effects 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 108090000623 proteins and genes Proteins 0.000 abstract description 3
- 102000004169 proteins and genes Human genes 0.000 abstract description 3
- 230000001603 reducing effect Effects 0.000 abstract description 3
- 230000004913 activation Effects 0.000 abstract description 2
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 238000013267 controlled drug release Methods 0.000 abstract 1
- 239000003607 modifier Substances 0.000 abstract 1
- 239000002861 polymer material Substances 0.000 abstract 1
- 238000001179 sorption measurement Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical group OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108010001515 Galectin 4 Proteins 0.000 description 1
- 102100039556 Galectin-4 Human genes 0.000 description 1
- 239000008777 Glycerylphosphorylcholine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000012756 surface treatment agent Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- MEYZYGMYMLNUHJ-UHFFFAOYSA-N tunicamycin Natural products CC(C)CCCCCCCCCC=CC(=O)NC1C(O)C(O)C(CC(O)C2OC(C(O)C2O)N3C=CC(=O)NC3=O)OC1OC4OC(CO)C(O)C(O)C4NC(=O)C MEYZYGMYMLNUHJ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/095—Compounds containing the structure P(=O)-O-acyl, P(=O)-O-heteroatom, P(=O)-O-CN
- C07F9/097—Compounds containing the structure P(=O)-O-N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- 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
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Birds (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Dermatology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Crystallography & Structural Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a phosphorylcholine compound Lys-PC containing propyl dimethicone and a preparation method thereof. The phosphorylcholine compound can be used as a surface treating agent or a raw material of the surface treating agent, can be directly used as a modifier for surfaces of various base materials or a chain extender and a cross-linking agent of modification of the base materials, can lower adsorption of protein, can improve the biocompatibility of high polymer materials by reducing adhesion and activation of blood platelets and has huge academic value and wide application prospects in the fields such as tissue engineering, controlled drug release, gene therapy and cosmetics. The steps are simple, the operation is convenient and the practicability is high.
Description
Technical field
The invention belongs to Phosphorylcholine derivant preparation field, more particularly to a kind of Phosphorylcholine chemical combination containing double amino
Thing Lys-PC and preparation method thereof.
Background technology
Phosphorylcholine is the terminal hydrophyllic group for constituting the soft phospholipid of membrane structure unit, is the outer layer sense in extracellular tunic
Group, simultaneous with positive and negative xenogenesis electric charge, the ability with stronger combination water and hydrophilicity, the table of this structure and composition
Face is interacted with physiological environment and will not only be adsorbed and depositing proteins, will not also be caused platelet activation, be caused blood coagulation etc.
Untoward reaction, with good biocompatibility.Research in recent years shows, using Phosphorylcholine group and its polymer in material
Material surface construction has anti-cell outer-layer membrane structure, can reduce the absorption of Fibrinogen, and by reducing hematoblastic sticking
Increase the biocompatibility of matrix material with activation.
Therefore in recent years, in order to improve the various functions such as the biocompatibility for improving material, water-retaining property, water absorption, people
Just energetically exploitation imported can with various substrate surfaces reacted it is reactive group, contain phosphinylidyne as dressing agent
The compound of the similar group of choline.For example, patent documentation 1 (CN201310106363.9) discloses a kind of phosphinylidyne gallbladder of hydroxyl
Alkali L- α-glyceryl phosphoryl choline crystal-form compound, patent documentation 2 (CN200580040742.6) disclose a kind of carboxylic phosphorus
The compound of phatidylcholine, patent documentation 3 (CN201310251000.4) disclose a kind of Phosphorylcholine compound containing aldehyde radical.
Though the compound disclosed in above-mentioned patent documentation has imported various functions group, entering with substrate surface treatment agent
During row chemical bonding, under existing technical conditions, must also there is the functional group being complementary in substrate surface, if desired for presence
Amino.If these compounds do not have the help of amino, its response rate can be very low, it is therefore desirable to the reaction of long-time and high temperature
Condition, or grafting process can not be carried out.
Therefore patent documentation 4 (CN201180062050.7) disclose a kind of Phosphorylcholine compound containing mono amino and
Its preparation method, but this kind of compound application still has limitation.This kind of compound only has mono amino functional group, is only capable of conduct
Surface conditioning agent is used for the grafting of substrate surface, and reactivity is relatively low, it is impossible to presence steady in a long-term, additionally, due to mono amino
This kind of compound of limitation cannot function as chain extender or cross-linking agent, so as to can not from material body improve bioaffinity.
The content of the invention
In order to overcome above-mentioned deficiency, the present invention provides a kind of new Phosphorylcholine compound can be directly as the table of material
Face inorganic agent, and as the chain extender and cross-linking agent of material, makes the material containing Phosphorylcholine disguise oneself as the natural component of surrounding,
Can reduce the absorption of Fibrinogen, and hematoblastic stick and activate the bio-compatible that increases matrix material by reducing
Property.
To achieve these goals, the present invention is adopted the following technical scheme that：
A kind of 1B is the Phosphorylcholine compound containing double amino (referred to as Lys-PC) of initiation material synthesis,
This new compound end-blocking with double amino, the Phosphorylcholine group which contains in addition, can make material disguise oneself as it is natural into
Point, its structural formula is as follows：
Here the synthesis of the Phosphorylcholine compound of double amino, from the 1B in gal4 amino acid as starting
Raw material, 1B compare D-Lys and other aminoacid containing polyamino, and its raw material is easy to get, and cost is lower；L- relies in addition
Propylhomoserin contains the aminoacid of double amino, such as agedoite, glutamine, citrulline etc. relative to other, its water-soluble and has
More preferably, structure is simpler for machine thing dissolubility, and in other polyamino aminoacid, second group containing amino is mostly acyl
Amido, amide groups activity are less than amino more, it is difficult to passing through chemical method is changed into amino by amide groups, therefore they are not
The optimum selection of this kind of pair of amino Phosphorylcholine compound of synthesis.
Present invention also offers a kind of preparation method of the Phosphorylcholine compound containing double amino, including：
With 1B as raw material, two amino on lysine are protected, obtain the compound (1) of carboxy blocking；
Under conditions of catalyst is present, the compound (1) of carboxy blocking is reduced into into hydroxy-end capped compound (2)；
Compound (2) and 2- oxo -1,3,2- dioxaphospholane (COP) is made to react at low temperature, the chemical combination for obtaining
Thing (3)；
Compound (3) is carried out into ring-opening reaction, hydrogenolysis and takes off amido protecting group, obtain final product the Phosphorylcholine containing double amino
Compound.
Preferably, the amido protecting group is Cbz groups, tertbutyloxycarbonyl (Boc), p-toluenesulfonyl (Tosyl)
Or fluorenylmethyloxycarbonyl (Fmoc).
Preferably, the catalyst is N-methylmorpholine.
Synthetic route is as follows：
1. with 1B as initiation material, the aqueous sodium carbonate using 10%-20% as solvent, preferred chloro-carbonic acid benzyl
Ester (Cbz-Cl) protective agent is protected to two amino on lysine, generates N, the double benzyloxycarbonyl group -1Bs of N'-.This
In protect amino functional group also have tertbutyloxycarbonyl (Boc), p-toluenesulfonyl (Tosyl), fluorenylmethyloxycarbonyl (Fmoc) etc.；
The target compound for obtaining, carries out extraction from organic solvents such as dichloromethane, chloroform, dimethyl sulfoxide and can obtain pure
The product of Du Genggao：
Double benzyloxycarbonyl group-the 1Bs of 2.N, N'- are dissolved in tetrahydrofuran or acetonitrile, preferred sodium borohydride (NaBH4) conduct
Reducing agent, with the help of catalyst (the preferred N-methylmorpholine of catalyst), reaction temperature is controlled at-10-- 20 DEG C, by carboxyl
The compound (1) of end-blocking is reduced into hydroxy-end capped compound (2), and which can carry out purification by known method, such as uses successively
Dilute hydrochloric acid, saturated aqueous common salt, distilled water wash choose the Methods For Purification of organic solvent column chromatography：
3. the hydroxy-end capped compound (2) for being obtained with second step is dissolved in anhydrous tetrahydro furan, by 2- oxo -1,3,2- bis-
Oxygen phospholane (COP) is dropped to wherein, and compound (2) is controlled 1 with the amount rate of charge of the material of COP:1～1:1.9；Protect
- 10 DEG C of--25 DEG C of reaction 1-3h of temperature are held, by-product triethylamine hydrochloride is filtered, the compound for obtaining (3) can pass through static,
Recrystallized from acetonitrile, the method purification of acetone recrystallization：
4. the product obtained in step 3 is dissolved in into acetonitrile, -20 DEG C of keeping temperature in reaction bulb rapidly join trimethylamine,
Ring-opening reaction 16-24h is carried out at 50-70 DEG C, then hydrogenolysis is taken off Cbz groups and final product compound (Lys-PC) obtained containing double ammonia
The Phosphorylcholine compound of base, hydrogenolysis method hydrogen bromide (HBr) used acidolysis, palladium charcoal (Pd/C) catalytic hydrogenation (palladium carbon content
5% -20%) etc., here as the reaction of hydrogen bromide acidolysis has by-product to produce, final product has dyeing, therefore we select
The method of catalytic hydrogenation.
Present invention also offers the Phosphorylcholine compound containing double amino prepared by arbitrary above-mentioned method.
Present invention also offers a kind of surface conditioning agent, including：The above-mentioned Phosphorylcholine containing double amino of any one
Compound.
Present invention also offers a kind of chain extender or cross-linking agent, including：The above-mentioned phosphinylidyne gallbladder containing double amino of any one
Alkali cpd.
Present invention also offers the above-mentioned Phosphorylcholine compound containing double amino of any one, surface conditioning agent, chain extension
Connect or cross-linking agent is preparing cosmetics, and organizational project, medicine controlled releasing, the application in gene therapy.
Beneficial effects of the present invention
(1) new compound of the invention is the Phosphorylcholine compound with double amino structures, is that application is high
Compound.Itself can serve as surface conditioning agent, can be as the dressing agent reacted with various substrate surfaces, due to containing
There are double amino, thus improve the Activity and stabill of reaction, dramatically play on material surface and adapted to organism
The surface modified function of the Phosphorylcholine base to represent.For example suppress protein absorption and reduce the soil resistances such as blood coagulation.
(2) using the superiority of the double amino of new compound of the invention, with reference to amino response characteristic (such as nucleophilic displacement of fluorine
Reaction, additive reaction, conjugation substitution reaction etc.), as cross-linking agent or chain extender, and then can obtain various new matrix material
Material, itself improves biocompatibility from material, Phosphorylcholine group is existed long-term and stably, farthest play phosphorus
The function of phatidylcholine group.
(3) the preparation method is that using the 1B of nonhazardouss as initiation material, it is ensured that the compound
Nonhazardouss in medical material are applied to, the lysine in human body also will not produce infringement to human body even if material generation is degraded.
(4) reaction raw materials of the present invention are easy to get, and quantitatively carry out, and high income, step are although more, but purification step is easy.
Specific embodiment
By the following examples feature of present invention and other correlated characteristics are described in further detail, in order to the same industry
The understanding of technical staff：
Embodiment 1
Step 1, the Cbz-Cl of 0.155mol are dissolved in the diethyl ether solution of 100mL, are added dropwise to 200mL containing 0.0645mol
The 10%NaCO of 1B3Aqueous solution, drips 0 DEG C of rear keeping temperature reaction 5h, and the product for obtaining is with appropriate 10% Fructus Citri Limoniae
Chloroform extraction is used after acid acidifying, is evaporated after reaction layer washing and is obtained a large amount of N, the double benzyloxycarbonyl group -1Bs of N'- are produced
Rate about 95%.
Step 2,0.06mol N are taken, the double benzyloxycarbonyl group -1Bs of N'- and 8mL N-methylmorpholines pour 500mL into anti-
In answering bottle, and 200mL tetrahydrofurans are dissolved in, reaction temperature is down to after -15 DEG C the chloromethyl isobutyl ester for adding 0.08mol, stirring
0.38mol sodium borohydrides, the Deca distilled water in reaction bulb is added until no bubble is produced, to continue stirring, room after 15min
The lower reaction 2h of temperature；Take out reaction solution and use dilute hydrochloric acid successively, saturated aqueous common salt, distilled water wash are finally dry with anhydrous magnesium sulfate
It is dry, boil off after solvent obtains crude product, purified with petrol ether/ethyl acetate column chromatography, purity is 96%, yield about 61.5%.
Step 3, product 0.389mol obtained by previous step is taken, poured in 500mL there-necked flasks, with the anhydrous tetrahydrochysene furans of 250mL
Mutter dissolving, after adding 0.389moL triethylamines, keep -15 DEG C of reaction temperature, under mechanical agitation, use constant pressure funnel Deca
The 50mL tetrahydrofuran solutions of 0.389mol COP, after dripping, are further continued for reacting 1.5h in 0.5h, and reduce pressure sucking filtration, is evaporated
To glassy yellow oil sticky mass.Yield about 82%.
Step 4, the product in heatproof, pressure reaction bulb in addition 0.05mol steps 3, the dry second eyeballs of 60mL and magneton,
Put it in freezer compartment of refrigerator, trimethylamine (0.075mol) is added thereto to rapidly after making reactant liquor be cooled to -20 DEG C, suitably
Excessive, sealing is placed, and reacting liquid temperature is recovered to room temperature.Under magnetic agitation, it is placed in 60 DEG C of oil baths and reacts.After reaction 24h
Yellow solution is poured out, is cooled down as refrigerator lower floor and slowly separate out crystallization, crude product dry acetonitrile recrystallization, yield about 91.9%.
Step 5,0.05mol compounds (4) are dissolved in 250mL absolute methanols, after stirring 15min, add under hydrogen shield
Excessive 15%Pd/C, after under room temperature, reaction terminates, solids removed by filtration obtains filtrate, and rotary evaporation removes solvent, uses dry acetonitrile
Recrystallization, obtains final product compound (1) Lys-PC yields about 87%.1H NMR (DMSO, TMS, 400MHz, ppm) δ：5.15
(4H, NH2—)；4.13-4.38 (t, 2H ,-CH2OP—)；3.13 (s, 9H ,-N+(CH3)3)；2.65 (br, 3H,
NH2CH2- ,-CH (NH2)—)；1.25-1.55 (br, 6H ,-CH2CH2CH2—)。
Finally it should be noted that the foregoing is only the preferred embodiments of the present invention, this is not limited to
Bright, although being described in detail to the present invention with reference to the foregoing embodiments, for a person skilled in the art, which is still
Technical scheme described in previous embodiment can be modified, or equivalent is carried out to which part.It is all at this
Within bright spirit and principle, any modification, equivalent substitution and improvements made etc. should be included in protection scope of the present invention
Within.Although the above-mentioned specific embodiment to the present invention is described, not limiting the scope of the invention, institute
Category art personnel should be understood that on the basis of technical scheme those skilled in the art need not pay wound
The various modifications made by the property made work or deformation are still within protection scope of the present invention.
Claims (8)
1. a kind of Phosphorylcholine compound containing double amino, it is characterised in that structural formula is as follows：
2. a kind of preparation method of the Phosphorylcholine compound containing double amino, it is characterised in that include：
With 1B as raw material, two amino on lysine are protected, obtain the compound (1) of carboxy blocking；
Under conditions of catalyst is present, the compound (1) of carboxy blocking is reduced into into hydroxy-end capped compound (2)；
Compound (2) and 2- oxo -1,3,2- dioxaphospholane (COP) is made to react at low temperature, the compound for obtaining
(3)；
Compound (3) is carried out into ring-opening reaction, hydrogenolysis and takes off amido protecting group, obtain final product the Phosphorylcholine chemical combination containing double amino
Thing.
3. method as claimed in claim 2, it is characterised in that the amido protecting group is Cbz groups, tertbutyloxycarbonyl
(Boc), p-toluenesulfonyl (Tosyl) or fluorenylmethyloxycarbonyl (Fmoc).
4. method as claimed in claim 2, it is characterised in that the catalyst is N-methylmorpholine.
5. the Phosphorylcholine compound containing double amino that prepared by the method described in any one of claim 2-4.
6. a kind of surface conditioning agent, it is characterised in that include：The Phosphorylcholine containing double amino described in claim 1 or 5
Compound.
7. a kind of chain extender or cross-linking agent, it is characterised in that including the phosphinylidyne gallbladder containing double amino described in claim 1 or 5
Alkali cpd.
8. the Phosphorylcholine compound containing double amino described in claim 1 or 5, the surface conditioning agent described in claim 6,
Chain extension described in claim 7 connects or cross-linking agent is preparing cosmetics, and organizational project, medicine controlled releasing, in gene therapy
Using.
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