CN108299499A - A kind of phosphatidyl ethanol amine molecule and preparation method thereof of pH sensitivities - Google Patents
A kind of phosphatidyl ethanol amine molecule and preparation method thereof of pH sensitivities Download PDFInfo
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- 230000035945 sensitivity Effects 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 150000008104 phosphatidylethanolamines Chemical class 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 238000006467 substitution reaction Methods 0.000 claims abstract description 7
- 230000003647 oxidation Effects 0.000 claims abstract description 6
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 5
- 230000005494 condensation Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 150000003536 tetrazoles Chemical class 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical group C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- -1 phosphatidyl ethanols Chemical class 0.000 claims description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 8
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical class C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 8
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 7
- 239000007832 Na2SO4 Substances 0.000 claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- 239000011574 phosphorus Substances 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 23
- 239000002502 liposome Substances 0.000 abstract description 16
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 abstract description 7
- 150000003904 phospholipids Chemical class 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 5
- 231100001083 no cytotoxicity Toxicity 0.000 abstract description 4
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000012377 drug delivery Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 239000008346 aqueous phase Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 5
- 150000001241 acetals Chemical class 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000013517 stratification Methods 0.000 description 5
- 239000013557 residual solvent Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000002706 plastid Anatomy 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- BRQFZWWIOXUTTD-UHFFFAOYSA-N benzene;dimethoxymethane Chemical compound COCOC.C1=CC=CC=C1 BRQFZWWIOXUTTD-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses phosphatidyl ethanol amine molecules of a kind of pH sensitivities and preparation method thereof, belong to the scope of drug delivery system in pharmaceutical chemistry.More particularly to a kind of phospholipid molecule of Novel pH Sensitive shown in formula 1, the molecule can form liposome in aqueous phase solvent, due to containing ethylidene ether structure in the molecule, and acetal bonds are more sensitive to acid, so that liposome can be dissociated quickly in acidic environment, to achieve the purpose that quick release loaded article.The synthesis of 1 compound of formula be using 2 compound of formula be starting material through condensation, substitution, oxidation obtain 5 compound of formula, finally under alkaline condition hydrolysis obtain 1 compound of target formula.The features such as synthetic method has easy to operate, high income, and purity is good, more conducively industrialized production.1 compound of the formula has aromatic ring structure (can develop the color under ultraviolet), is easy to detect, and almost the features such as no cytotoxicity, is relatively beneficial to the medicinal materials as pH sensitivities.
Description
Technical field
The present invention relates to biomedicine technical field, the phosphatidyl-ethanolamine more particularly to a kind of pH sensitivities and preparation side
Method and application.
Background technology
Phosphatide is a lipoid plastid, it is the main component of all cell membranes, and phosphatide is amphiphatic molecule, and one end is hydrophilic
Nitrogenous or phosphorus head, the other end are that the long hydrocarbyl chain of hydrophobic (oleophylic) forms, both components are connected to one by glycerol molecule
Playing phosphate group can be modified with simple organic molecule such as choline.
Phosphatide has been widely used for preparing part, takes orally the liposome with parenteral drug, zoarium and other nanometer formulations,
Reason is different, the bioavilability such as improved, the toxicity of reduction and increased transmembranal penetration.Since conventional liposome is single
Pure passive target is easily swallowed by the degradation of some enzyme materials and macrophage, cannot reach target tissue and effectively send out in vivo
Drug effect is waved, haves the shortcomings that targeting is poor.
It will appear abnormal acidification phenomenon at inflammation or infected zone, certain tumor tissues or ischaemic, and pH is sensitive
The stability of lipid bilayer in type liposome structure changes with environment pH variations, unstable in acidic environment, this
Just the shortcomings that compensating for conventional liposome, improves the targeting of liposome, can promote giving full play to and improving base for drug effect
The expression of cause has good application value in drug delivery system.
Phosphatidyl-ethanolamine (PE) is also known as cephalin, and cephalin has good reproducibility, therefore is a kind of functional
Antioxidant, applied in terms of medical field and its extensively.
Invention content
In order to overcome drawbacks described above in the prior art, one of the object of the invention to be to provide one kind using pentaerythrite as skeleton
Novel pH Sensitive phospholipid molecule, the pH sensitivities phospholipid molecule be acid-sensitive phosphatidyl ethanol amine molecule, to solve existing skill
It synthesizes complicated in art, is not easy to detect, the problems such as to the difference in response of acid.
Another object of the present invention proposes a kind of phosphatidyl ethanol amine molecule i.e. synthesis of 1 compound of formula of synthesis pH sensitivities
Method.It is starting material through condensation using 2 compound of formula, substitution, oxidation obtains 5 compound of formula, finally water under alkaline condition
Solution obtains 1 compound of target formula.The synthetic method has easy to operate, high income (two step total recoverys are up to 75-83%), pure
The features such as having spent, more conducively industrialized production.1 compound of the formula has aromatic ring structure (can develop the color under ultraviolet), is easy to
Detection almost the features such as no cytotoxicity, is relatively beneficial to the medicinal materials as pH sensitivities.
The object of the present invention is achieved like this：
A kind of pH sensitivities phosphatidyl ethanol amine molecule, structural formula are as shown in Equation 1：
Wherein, R is the alkyl of C9~C17.Preferably, the R is the aliphatic alkyl of straight chain saturation, that is, preferably, institute
The molecular structure for stating Novel pH Sensitive phosphatidyl-ethanolamine is：
The synthetic route of pH sensitivities phosphatidyl ethanol amine molecule of the present invention, as follows：
Its specific preparation process includes the following steps：
Step a：
I) under the action of solvent and tetrazole, 3 intermediate of condensation reaction production occurs for 2 compound of formula and phosphorus reagent；
Ii) in same reaction system, 3 intermediate of formula is in the presence of tetrazole, with (9H- fluorenes -9- bases) methyl (2- hydroxyls
Ethyl) 4 intermediate of substitution reaction production occurs for carbamate；
Iii) in same reaction system, under the action of metachloroperbenzoic acid (m-CPBA) oxygen occurs for 4 intermediate of formula
Change reaction 5 compound of production；
Step b：
5 compound of formula phosphatide head base under the action of solvent and alkali occurs hydrolysis and obtains target compound phosphatidyl-ethanolamine
As shown in Equation 1.
Reaction process is as shown in synthetic route：
Wherein, in step a,
The reaction dissolvent is that dichloromethane, chloroform etc. are more preferably dichloromethane.
In step i), the phosphorus reagent is 2- cyanoethyls N, N, N', N'- tetraisopropylphosph-ro phosphoryl diamine, the tetrazole
For 1H- tetrazoles；The reaction temperature is 0 DEG C~40 DEG C, is 20 DEG C more preferably；2 compound of the formula, phosphorus reagent, tetrazole
Molar ratio be 1.0 ︰, 1.0~2.0 ︰ 1.0~2.0, more preferably, be 1.0 ︰, 1.3 ︰ 1.3；
Step ii) in, the reaction temperature is 0 DEG C~40 DEG C, is 20 DEG C more preferably；2 compound of the formula, (9H- fluorenes-
9- yls) methyl (2- ethoxys) carbamate, tetrazole molar ratio be 1.0 ︰, 1.0~2.0 ︰ 1.0~2.0 be more preferably
1.0 ︰, 1.3 ︰ 1.3；
Step iii) in, the reaction temperature is 0 DEG C~40 DEG C, is 20 DEG C more preferably；The oxidant is m-chloro peroxide
Benzoic acid (m-CPBA)；2 compound of the formula, metachloroperbenzoic acid (m-CPBA) molar ratio are 1.0 ︰ 1.0~2.0, more excellent
Ground is 1.0 ︰ 2.0.Preferably, further comprising the steps of after the completion of the condensation, substitution, oxidation three-step reaction in step a：
The Na with m-CPBA equivalents is added to system2SO3Solution, after stirring 30min, liquid separation is washed with 1M HCl, is saturated successively
NaHCO3Solution washs, organic phase anhydrous Na2SO4It is dry, it is evaporated to obtain crude product, is beaten with methanol, 5 compound of white solid formula is obtained.
Wherein, in step b,
The reaction temperature is 0 DEG C~40 DEG C, is 20 DEG C more preferably；The alkali is DBU, triethylamine, NaOH, DIEA etc.,
More preferably, it is DBU；The reaction dissolvent is that dichloromethane, chloroform etc. are more preferably dichloromethane.Preferably, step b
In, it is further comprising the steps of after the completion of the hydrolysis：The ice AcOH solution with DBU equivalents, stirring is added to system
After 5min, solvent evaporated is taken residual solvent out of with methanol, is then beaten with ethyl acetate, and 1 compound of white solid formula is obtained.
Compared with prior art, the invention has the advantages that：
(1) new pH sensitivity phospholipid molecules provided by the invention, due to the acetal with acid-sensitive, the acetal is in weak acid
Property or acid medium in acetal in the phosphatide be easily broken, therefore, the pH sensitivities phospholipid molecule is situated between in neutral or alkalescent
Stability is high in matter, has good pH sensibility in faintly acid or acid medium.
(2) pH sensitivities phospholipid molecule of the present invention has good biocompatibility, no cytotoxicity.
(3) present invention is that a kind of phosphatidyl-ethanolamine of pH sensitivities is as shown in Equation 1, due to containing acetal knot in the molecule
Structure, and acetal bonds are more sensitive to acid so that liposome can be dissociated quickly in acidic environment, to reach quick release load
The purpose of object, and the compound has aromatic ring structure (can develop the color under ultraviolet), is easy to detect, almost the spies such as no cytotoxicity
Point is relatively beneficial to the medicinal materials as pH sensitivities.
(4) present invention using 2 compound of formula be starting material through through condensation, substitution, oxidation obtain 5 compound of formula, finally
Hydrolysis obtains 1 compound of target formula under alkaline condition.The method of the present invention synthetic route is brief, and cost is relatively low, and condition is easily-controllable, after
Processing is simple, and by-product is few, and purity is higher, and yield is higher, and two step total recoverys can reach 50%-83%, the feasibility of the route
It is stronger, it is easy to industrialized production.
Description of the drawings
Fig. 1, Fig. 2 are change of size figure of the liposome in different pH buffer solutions obtained by embodiment 4；
Fig. 3 is 1 compound of formula when pH is 4.51The Dynamic Graph that H-NMR chemical shifts change over time.
Specific implementation mode
In order to be more clearly understood that the technology contents of the present invention, it is further described below in conjunction with embodiment：
Embodiment 1
The preparation of 1.1 formula, 5 compound
Under nitrogen protection, by 2 compound of formula (0.33g, 0.43mmol), 2- cyanoethyls N, N, N', N'- tetra isopropyl phosphorous
Be added in the dichloromethane (6mL) that acid diamide (0.17g, 0.56mmol) is dissolved in, at 20 DEG C 1-H tetrazoles (0.04g,
0.56mmol), 1h is reacted at 20 DEG C；Then (9H- fluorenes -9- bases) methyl (2- ethoxys) carbamate is added into system
(0.16g, 0.56mmol), 1-H tetrazoles (0.04g, 0.56mmol), 20 DEG C are reacted 1.5 hours, and m-chloro mistake is added into system
20 DEG C of reaction 0.5h of oxybenzoic acid (m-CPBA) (0.15g, 0.87mmol).After TLC detection raw materials completely disappear, it is sub- that saturation is added
Sodium sulphate (0.03g, 0.87mmol) solution, stirs 30min, and stratification is washed with 1M HCl, is saturated NaHCO successively3Solution
Washing, organic phase anhydrous Na2SO4It is dry, it is evaporated to obtain crude product, is beaten with methanol, 5 compound 0.45g of white solid formula, yield are obtained：
90%.1H NMRδ:7.75 (d, J=7.5Hz, 2H), 7.59 (d, J=7.3Hz, 2H), 7.39 (t, J=7.4Hz, 2H), 7.31
(t, J=7.4Hz, 2H), 6.10 (s, 2H), 5.96 (s, 1H), 5.36 (s, 1H), 4.64 (s, 2H), 4.40 (d, J=6.6Hz,
4H), 4.26-4.12 (m, 7H), 4.07 (d, J=11.3Hz, 2H), 3.91 (s, 2H), 3.80 (m, 6H), 3.49 (s, 2H),
2.70 (t, J=6.1Hz, 2H), 2.30-2.34 (m, 4H), 1.25 (m, 46H), 0.88 (t, J=6.6Hz, 6H)；
HR-ESI-MS m/z:Calcd for C64H95N2O15PNa{[M+Na]+}1185.6362,found
1185.6348。
The preparation of 1.2 formula, 5 compound
Under nitrogen protection, by 2 compound of formula (0.33g, 0.43mmol), 2- cyanoethyls N, N, N', N'- tetra isopropyl phosphorous
Be added in the dichloromethane (6mL) that acid diamide (0.17g, 0.56mmol) is dissolved in, at 20 DEG C 1-H tetrazoles (0.04g,
0.56mmol), 1h is reacted at 0 DEG C；Then (9H- fluorenes -9- bases) methyl (2- ethoxys) carbamate is added into system
(0.16g, 0.56mmol), 1-H tetrazoles (0.04g, 0.56mmol), 0 DEG C is reacted 1.5 hours, and m-chloro mistake is added into system
0 DEG C of reaction 0.5h of oxybenzoic acid (m-CPBA) (0.15g, 0.87mmol).After TLC detection raw materials completely disappear, it is sub- that saturation is added
Sodium sulphate (0.03g, 0.87mmol) solution, stirs 30min, and stratification is washed with 1M HCl, is saturated NaHCO successively3Solution
Washing, organic phase anhydrous Na2SO4It is dry, it is evaporated to obtain crude product, is beaten with methanol, 5 compound 0.36g of white solid formula, yield are obtained：
72%.1H NMRδ:7.75 (d, J=7.5Hz, 2H), 7.59 (d, J=7.3Hz, 2H), 7.39 (t, J=7.4Hz, 2H), 7.31
(t, J=7.4Hz, 2H), 6.10 (s, 2H), 5.96 (s, 1H), 5.36 (s, 1H), 4.64 (s, 2H), 4.40 (d, J=6.6Hz,
4H), 4.26-4.12 (m, 7H), 4.07 (d, J=11.3Hz, 2H), 3.91 (s, 2H), 3.80 (m, 6H), 3.49 (s, 2H),
2.70 (t, J=6.1Hz, 2H), 2.30-2.34 (m, 4H), 1.25 (m, 46H), 0.88 (t, J=6.6Hz, 6H)；HR-ESI-MS
m/z:Calcd for C64H95N2O15PNa{[M+Na]+}1185.6362,found 1185.6348。
The preparation of 1.3 formula, 5 compound
Under nitrogen protection, by 2 compound of formula (0.33g, 0.43mmol), 2- cyanoethyls N, N, N', N'- tetra isopropyl phosphorous
Be added in the dichloromethane (6mL) that acid diamide (0.17g, 0.56mmol) is dissolved in, at 20 DEG C 1-H tetrazoles (0.04g,
0.56mmol), 1h is reacted at 40 DEG C；Then (9H- fluorenes -9- bases) methyl (2- ethoxys) carbamate is added into system
(0.16g, 0.56mmol), 1-H tetrazoles (0.04g, 0.56mmol), 40 DEG C are reacted 1.5 hours, and m-chloro mistake is added into system
40 DEG C of reaction 0.5h of oxybenzoic acid (m-CPBA) (0.15g, 0.87mmol).After TLC detection raw materials completely disappear, it is sub- that saturation is added
Sodium sulphate (0.03g, 0.87mmol) solution, stirs 30min, and stratification is washed with 1M HCl, is saturated NaHCO successively3Solution
Washing, organic phase anhydrous Na2SO4It is dry, it is evaporated to obtain crude product, is beaten with methanol, 5 compound 0.43g of white solid formula, yield are obtained：
85%.1H NMRδ:7.75 (d, J=7.5Hz, 2H), 7.59 (d, J=7.3Hz, 2H), 7.39 (t, J=7.4Hz, 2H), 7.31
(t, J=7.4Hz, 2H), 6.10 (s, 2H), 5.96 (s, 1H), 5.36 (s, 1H), 4.64 (s, 2H), 4.40 (d, J=6.6Hz,
4H), 4.26-4.12 (m, 7H), 4.07 (d, J=11.3Hz, 2H), 3.91 (s, 2H), 3.80 (m, 6H), 3.49 (s, 2H),
2.70 (t, J=6.1Hz, 2H), 2.30-2.34 (m, 4H), 1.25 (m, 46H), 0.88 (t, J=6.6Hz, 6H)；HR-ESI-MS
m/z:Calcd for C64H95N2O15PNa{[M+Na]+}1185.6362,found 1185.6348.The system of 1.4 formula, 5 compound
It is standby
Under nitrogen protection, by 2 compound of formula (0.33g, 0.43mmol), 2- cyanoethyls N, N, N', N'- tetra isopropyl phosphorous
Be added in the dichloromethane (6mL) that acid diamide (0.26g, 0.86mmol) is dissolved in, at 20 DEG C 1-H tetrazoles (0.06g,
0.86mmol), 1h is reacted at 20 DEG C；Then (9H- fluorenes -9- bases) methyl (2- ethoxys) carbamate is added into system
(0.24g, 0.86mmol), 1-H tetrazoles (0.06g, 0.86mmol), 20 DEG C are reacted 1.5 hours, and m-chloro mistake is added into system
40 DEG C of reaction 0.5h of oxybenzoic acid (m-CPBA) (0.15g, 0.87mmol).After TLC detection raw materials completely disappear, it is sub- that saturation is added
Sodium sulphate (0.03g, 0.87mmol) solution, stirs 30min, and stratification is washed with 1M HCl, is saturated NaHCO successively3Solution
Washing, organic phase anhydrous Na2SO4It is dry, it is evaporated to obtain crude product, is beaten with methanol, 5 compound 0.45g of white solid formula, yield are obtained：
90%.1H NMRδ:7.75 (d, J=7.5Hz, 2H), 7.59 (d, J=7.3Hz, 2H), 7.39 (t, J=7.4Hz, 2H), 7.31
(t, J=7.4Hz, 2H), 6.10 (s, 2H), 5.96 (s, 1H), 5.36 (s, 1H), 4.64 (s, 2H), 4.40 (d, J=6.6Hz,
4H), 4.26-4.12 (m, 7H), 4.07 (d, J=11.3Hz, 2H), 3.91 (s, 2H), 3.80 (m, 6H), 3.49 (s, 2H),
2.70 (t, J=6.1Hz, 2H), 2.30-2.34 (m, 4H), 1.25 (m, 46H), 0.88 (t, J=6.6Hz, 6H)；HR-ESI-MS
m/z:Calcd for C64H95N2O15PNa{[M+Na]+}1185.6362,found 1185.6348。
The preparation of 1.5 formula, 5 compound
Under nitrogen protection, by 2 compound of formula (0.33g, 0.43mmol), 2- cyanoethyls N, N, N', N'- tetra isopropyl phosphorous
Be added in the dichloromethane (6mL) that acid diamide (0.17g, 0.56mmol) is dissolved in, at 20 DEG C 1-H tetrazoles (0.04g,
0.56mmol), 1h is reacted at 20 DEG C；Then (9H- fluorenes -9- bases) methyl (2- ethoxys) carbamate is added into system
(0.16g, 0.56mmol), 1-H tetrazoles (0.04g, 0.56mmol), 20 DEG C are reacted 1.5 hours, and m-chloro mistake is added into system
20 DEG C of reaction 0.5h of oxybenzoic acid (m-CPBA) (0.075g, 0.43mmol).After TLC detection raw materials completely disappear, saturation is added
Sodium sulfite (0.015g, 0.43mmol) solution, stirs 30min, and stratification is washed with 1M HCl, is saturated NaHCO successively3
Solution washs, organic phase anhydrous Na2SO4It is dry, it is evaporated to obtain crude product, is beaten with methanol, 5 compound 0.40g of white solid formula is obtained,
Yield：80%.1H NMRδ:7.75 (d, J=7.5Hz, 2H), 7.59 (d, J=7.3Hz, 2H), 7.39 (t, J=7.4Hz,
2H), 7.31 (t, J=7.4Hz, 2H), 6.10 (s, 2H), 5.96 (s, 1H), 5.36 (s, 1H), 4.64 (s, 2H), 4.40 (d, J
=6.6Hz, 4H), 4.26-4.12 (m, 7H), 4.07 (d, J=11.3Hz, 2H), 3.91 (s, 2H), 3.80 (m, 6H), 3.49
(m, 2H), 2.70 (t, J=6.1Hz, 2H), 2.30-2.34 (m, 4H), 1.25 (m, 46H), 0.88 (t, J=6.6Hz, 6H)；
HR-ESI-MS m/z:Calcd for C64H95N2O15PNa{[M+Na]+}1185.6362,found 1185.6348。
Embodiment 2
The preparation of 2.1 formula, 1 compound
5 compound of formula (0.1g, 0.086mmol) is dissolved in dichloromethane (5mL), at room temperature be added DBU (0.026g,
0.17mmol), it reacts 1.5 hours for 20 DEG C, TLC detections, raw material disappears.AcOH (0.11g, 0.19mmol) is added, stirs 5min
Afterwards, solvent evaporated is taken residual solvent out of with methanol, is then beaten with ethyl acetate, and 1 compound 0.073g of white solid formula is obtained,
Yield is 93%.1H NMRδ:6.07 (s, 2H), 5.93 (s, 1H), 4.62 (s, 2H), 4.13 (s, 2H), 4.06 (d, J=
11.1Hz,7H),3.89(s,2H),3.78(m,6H),3.41(m,2H),2.30-2.33(m,4H),1.96(s,2H),1.25
(s, 46H), 0.87 (t, J=6.6Hz, 6H)；HR-ESI-MS m/z:Calcd for C46H82NO13PNa{[M+Na]+}
910.5416,found 910.5389。
The preparation of 2.2 formula, 1 compound
5 compound of formula (0.1g, 0.086mmol) is dissolved in dichloromethane (5mL), triethylamine is added at room temperature
(0.017g, 0.17mmol), 20 DEG C are reacted 1.5 hours, and TLC detections, raw material disappears.AcOH (0.11g, 0.19mmol) is added,
After stirring 5min, solvent evaporated is taken residual solvent out of with methanol, is then beaten with ethyl acetate, and 1 compound of white solid formula is obtained
0.063g, yield 81%.1H NMRδ:6.07(s,2H),5.93(s,1H),4.62(s,2H),4.13(s,2H),4.06(d,
J=11.1Hz, 7H), 3.89 (s, 2H), 3.78 (m, 6H), 3.41 (m, 2H), 2.30-2.33 (m, 4H), 1.96 (s, 2H),
1.25 (s, 46H), 0.87 (t, J=6.6Hz, 6H)；HR-ESI-MS m/z:Calcd for C46H82NO13PNa{[M+Na]+}
910.5416,found 910.5389。
The preparation of 2.3 formula, 1 compound
5 compound of formula (0.1g, 0.086mmol) is dissolved in dichloromethane (5mL), at room temperature be added DIEA (0.022g,
0.17mmol), it reacts 1.5 hours for 20 DEG C, TLC detections, raw material disappears.AcOH (0.11g, 0.19mmol) is added, stirs 5min
Afterwards, solvent evaporated is taken residual solvent out of with methanol, is then beaten with ethyl acetate, and 1 compound 0.058g of white solid formula is obtained,
Yield is 74%.1H NMRδ:6.07 (s, 2H), 5.93 (s, 1H), 4.62 (s, 2H), 4.13 (s, 2H), 4.06 (d, J=
11.1Hz,7H),3.89(s,2H),3.78(m,6H),3.41(m,2H),2.30-2.33(m,4H),1.96(s,2H),1.25
(s, 46H), 0.87 (t, J=6.6Hz, 6H)；HR-ESI-MS m/z:Calcd for C46H82NO13PNa{[M+Na]+}
910.5416,found 910.5389。
Embodiment 3
1 compound of phosphatide formula prepared by embodiment 2, liposome is prepared using film evaporation method, takes phosphatide (compound 1)
10mg, cholesterol 2.3mg be dissolved in chloroform, alcohol mixed solution (volume ratio of chloroform and ethyl alcohol be 1：5), in Rotary Evaporators
On be slowly evaporated (1h), then proceed to vacuum drying 30min, so that organic solvent is removed completely.Thereto plus 100mMNaCl (is used
NaOH tune pH is to 7.5), 48 DEG C of aquation 10min, by liposome by LiposoFast mini-extruder extrusion instruments, the poly- carbonic acid through the apertures 200nm
Ester film squeezes out 10 times, obtains liposome solutions.
Embodiment 4
Four parts, every part of 10uL of liposome solutions obtained by Example 3, respectively use pH value be 7.4 (100mM NaCl,
50mM Na2HPO4/NaH2PO4), 6.0 (100mM NaCl, 50mM Na2HPO4/NaH2PO4)、5.0(100mM NaCl,50mM
NaAC/HAC), the buffer solution of 4.0 (100mM NaCl, 50mM NaAC/HAC) is diluted to 1ml, and monitoring liposome is in pH value
7.4, under the conditions of 6.0,5.0,4.0, grain size changes with time (as depicted in figs. 1 and 2).Such as the condition that Fig. 1 is 7.4 in pH
Under, for 24 hours after liposome grain size, still without more apparent variation, also in stable state, and under conditions of pH is 4.0, fat after 3h
Plastid is acid hydrolysis, and structure changes, and reunites and grain size is made to become larger.Such as Fig. 2, under the conditions of pH value is 5.0, grain size for 24 hours
Also it significantly increases, under the conditions of pH value is 6.0, grain size remains unchanged for 24 hours, illustrates that the liposome has certain acid-sensitive
Property.
Embodiment 5
It is molten to be dissolved in NaOAc/AcOH (500 μ L, 0.2M, pH 4.5) bufferings to 1 compound of phosphatide formula prepared by embodiment 2
In liquid, 500 μ L CD are added into the system3OD, the chemical shift for monitoring 1H-NMR at regular intervals change over time
The case where, as shown in figure 3, observation chart, during finding the hydrolysis of benzene dimethoxym ethane (hydrolysis equation is shown below), aldehyde radical
Hydrogen (H a') occurs and increases, and the hydrogen (H a) of acetal reduces.In addition, Hb' increases in hydrolytic process also with the reduction of Hb
Add.It follows that the compound has certain sensitivity to acid really.
In conclusion the present invention synthesize pH sensitivity phosphatidyl-ethanolamine method with synthetic line it is brief, cost compared with
Low, easy to operate, yield is high, the advantages of being easy to industrialized production；And the acid-sensitive characteristic being somebody's turn to do also is proved well, is one
A very potential medicinal materials as acid-sensitive.
The present invention is described in detail above, its object is to allow the personage for being familiar with this field technology that can understand this
The content of invention is simultaneously implemented, and it is not intended to limit the scope of the present invention, all Spirit Essence institutes according to the present invention
The equivalent change or modification of work should all cover within the scope of the present invention.
Claims (8)
1. a kind of pH sensitivities phosphatidyl ethanol amine molecule, which is characterized in that the structure of the phosphatidyl ethanol amine molecule such as 1 institute of formula
Show：
The aliphatic alkyl that the straight chain that wherein R is C9~C17 is saturated.
2. the preparation method of pH sensitivities phosphatidyl ethanol amine molecule described in a kind of claim 1, which is characterized in that this method includes
The following steps：
Step a：
I) under the action of solvent and tetrazole, 3 intermediate of condensation reaction production occurs for 2 compound of formula and phosphorus reagent；
Ii) in same reaction system, 3 intermediate of formula is in the presence of tetrazole, with (9H- fluorenes -9- bases) methyl (2- hydroxyl second
Base) 4 intermediate of substitution reaction production occurs for carbamate；
Iii) in same reaction system, under the action of metachloroperbenzoic acid (m-CPBA) oxidation occurs for 4 intermediate of formula anti-
Answer 5 compound of production；
Step b：
5 compound of formula phosphatide head base under the action of solvent and alkali occurs hydrolysis and obtains target compound pH sensitivity phosphatidyl ethanols
1 compound of amine molecule formula；
Wherein, reaction process is as follows：
3. preparation method according to claim 2, which is characterized in that the i of step a) in step, the solvent is dichloromethane
Alkane or chloroform；The phosphorus reagent is 2- cyanoethyls N, N, N', N'- tetraisopropylphosph-ro phosphoryl diamine, and the tetrazole is 1H-
Tetrazole；The reaction temperature is 0 DEG C~40 DEG C；2 compound of the formula, phosphorus reagent, tetrazole molar ratio be 1.0 ︰ 1.0~
2.0 ︰ 1.0~2.0.
4. preparation method according to claim 2, which is characterized in that the ii of step a) in step, the reaction temperature is 0
DEG C~40 DEG C；2 compound of the formula, (9H- fluorenes -9- bases) methyl (2- ethoxys) carbamate, tetrazole molar ratio be
1.0 ︰, 1.0~2.0 ︰ 1.0~2.0.
5. preparation method according to claim 2, which is characterized in that the iii of step a) in step, the reaction temperature is
0 DEG C~40 DEG C；The oxidant is metachloroperbenzoic acid (m-CPBA)；2 compound of the formula, metachloroperbenzoic acid (m-
CPBA molar ratio) is 1.0 ︰ 1.0~2.0.
6. preparation method according to claim 2, which is characterized in that in step a, the condensation, substitution, three steps of oxidation are anti-
It is further comprising the steps of after the completion of answering：The Na with m-CPBA equivalents is added to system2SO3Solution, after stirring 30min, liquid separation,
It washed successively with 1M HCl, be saturated NaHCO3Solution washs, organic phase anhydrous Na2SO4It is dry, it is evaporated to obtain crude product, is beaten with methanol
Slurry, obtains 5 compound of white solid formula.
7. preparation method according to claim 2, which is characterized in that in step b, the reaction temperature is 0 DEG C~40 DEG C；
The alkali is DBU, triethylamine, NaOH or DIEA；5 compound of the formula, the molar ratio of alkali are 1.0 ︰ 1.0~2.5；The solvent
For dichloromethane or chloroform.
8. preparation method according to claim 2, which is characterized in that in step b, after the completion of the hydrolysis, also wrap
Include following steps：The ice AcOH solution with DBU equivalents is added to system, after stirring 5min, solvent evaporated is taken out of residual with methanol
Remaining solvent, is then beaten with ethyl acetate, obtains 1 compound of white solid formula.
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