CN110128468A - A kind of synthetic method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines - Google Patents
A kind of synthetic method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines Download PDFInfo
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- CN110128468A CN110128468A CN201910531430.9A CN201910531430A CN110128468A CN 110128468 A CN110128468 A CN 110128468A CN 201910531430 A CN201910531430 A CN 201910531430A CN 110128468 A CN110128468 A CN 110128468A
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- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 37
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 150000008105 phosphatidylcholines Chemical class 0.000 title claims abstract description 28
- 238000010189 synthetic method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims abstract description 12
- ADHNUPOJJCKWRT-UHFFFAOYSA-N octadeca-2,4-dienoic acid Chemical compound CCCCCCCCCCCCCC=CC=CC(O)=O ADHNUPOJJCKWRT-UHFFFAOYSA-N 0.000 claims abstract description 11
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005886 esterification reaction Methods 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 125000003963 dichloro group Chemical group Cl* 0.000 claims abstract description 6
- 230000032050 esterification Effects 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 53
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 7
- 238000005917 acylation reaction Methods 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- 239000011574 phosphorus Substances 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- OACNVHUVISUWMV-UHFFFAOYSA-N C1(C=CC(C=C1)=O)=O.N#CC#N Chemical compound C1(C=CC(C=C1)=O)=O.N#CC#N OACNVHUVISUWMV-UHFFFAOYSA-N 0.000 claims 1
- 239000007809 chemical reaction catalyst Substances 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 abstract 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- -1 Methacryloyl Chemical group 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000005360 mashing Methods 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical class C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003012 bilayer membrane Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- GWLJTAJEHRYMCA-UHFFFAOYSA-N phospholane Chemical compound C1CCPC1 GWLJTAJEHRYMCA-UHFFFAOYSA-N 0.000 description 1
- 238000005954 phosphonylation reaction Methods 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The present invention discloses a kind of bis- (18 carbon -2; 4- dienoyl) phosphatidyl choline preparation method; it is related to field of compound preparation; the following steps are included: (1) is by chemical compounds I; that is 3- (4- mehtoxybenzyl oxygroup) -1; 2- propylene glycol and 2,4- octadecane dienoic acid occur esterification and generate compound ii；(2) compound ii and 2 that will be synthesized in step (1), chloro- 5, the 6- dicyanoquinone (DDQ) of 3- bis- mixing, generates compound III；(3) compound III synthesized in step (2) is reacted with B- bromoethyl phosphinylidyne dichloro and generates compounds Ⅳ；(4) it after the compounds Ⅳ synthesized in step (3) and trimethylamine gas reaction, will will be passed through solvent hair reaction and generate bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines.The beneficial effects of the present invention are: high income, total recovery are reduced costs up to 49%.
Description
Technical field
The present invention relates to technical field of compound preparation, and in particular to a kind of bis- (18 carbon -2,4- dienoyl) phosphatide
The preparation method of phatidylcholine.
Background technique
Bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines, abbreviation Bis-DienPC is a kind of dienoyl phosphatide,
It is received significant attention as the carrier of drug delivery system, can be used for entrapped drug, such as anticancer agent, protein and other lifes
Active substances.In addition, bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines poly- (lipid) vesica easy to form and plane branch
The bilayer of support, can significantly improve Surfactant, solvent, the stability of long term storage, such phosphatide can crosslink polymerization,
Compared to the stability that linear polymerization can significantly increase film, change the permeability of ion and small molecule.So developing one
Economical and practical, preparation method easy to operate has very important meaning and value.
Synthesis about phosphatidyl choline intermediate has pertinent literature report.Bis- (the 18 carbon -2,4- of document report at present
Dienoyl) phosphatidyl choline synthetic route there are two types of.Document JPNES, I.W.and HALL
Jr.H.K..Demonstration of a convergent approach to UV-polymerizable lipids
BisDenPC and bisSorbPC [J] .Tetrahedron Letters, 2011,52,3699-3701, the route recorded
One as shown in Figure 1,18 carbon -2,4- dienoic acids and (R) -3- benzyloxy -1,2-PD obtain chemical combination under the action of DMAP
Object (2), then, low temperature (- 78 DEG C) debenzylation under boron chloride effect, then reacted with ring phospholane, then lead to front three
Amine gas obtains target compound (3).
Document HEITZ B.A., JONES I.W., HALL H.K., et al.Fractional polymerization
of a suspended planar bilayer creates a fluid,highly stable membrane for ion
Channel recordings [J] .J.AM.CHEM.SOC., 2010,132,7086-7093 and Dorn K., Klingbiel
R.T.,Specht D.P..Permeability Characteristics of Polymeric Bilayer Membranes
In from Methacryloyl and Butadiene Lipids [J] .J.AM.CHEM.SOC., 1984,106,1627-1633
The route two of record under DCC effect, is condensed to yield corresponding acid anhydrides as shown in Fig. 2, with compound (1) for starting material
(4), target compound (3) then are condensed to yield with glycerolphosphocholine (GPC) under DMAP effect.Synthesisization in the program
The yield for closing object (4) only has 25%, and while being condensed with GPC will lose the compound (1) of a molecule, and Atom economy is poor, receives
Rate is low, at high cost.
Summary of the invention
Present invention solves the technical problem that being the synthesis of existing bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines
Method yield is low, at high cost.
As shown in figure 3, Fig. 3 is the synthetic route chart of bis- (18 carbon -2, the 4- dienoyl) phosphatidyl cholines of the present invention.
The present invention adopts the following technical solutions solves above-mentioned technical problem:
The present invention provides a kind of preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines, including following step
It is rapid:
(1) by chemical compounds I, i.e. 3- (4- mehtoxybenzyl oxygroup) -1,2-PD and 2,4- octadecane dienoic acid hair
Raw esterification generates compound ii；
(2) compound ii and 2 that will be synthesized in step (1), chloro- 5, the 6- dicyanoquinone (DDQ) of 3- bis- mixing, occurs ether
Deprotection reaction generate compound III；
(3) phosphorus acylation reaction is occurred into for the compound III and B- bromoethyl phosphinylidyne dichloro that synthesize in step (2) and generates chemical combination
Object IV；
(4) after hydrolysis being occurred for the compounds Ⅳ and front three amine gas that synthesize in step (3), final product is generated
V, i.e., bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines.
Preferably, solvent used in the esterification reaction process of the step (1) includes methylene chloride (DCM), the ester
Changing condensing agent used in reaction process is dicyclohexylcarbodiimide (DCC) or 1- (3- dimethylamino-propyl) -3- ethyl carbon
Diimmonium salt hydrochlorate (EDCI)；Catalyst used in the esterification reaction process is 4-dimethylaminopyridine (DMAP).
Preferably, the molar ratio of step (1) chemical compounds I and condensing agent is 2:2.5.
Preferably, the reaction temperature in the step (1) is 10-20 DEG C, reaction time 7-9h.
Preferably, the compound ii generated in step (1) is purified, the purification step includes suction filtration, acidification, extraction
It takes, dry, be evaporated.
Preferably, the solvent that deprotection reaction uses in the step (2) is methylene chloride (DCM), the compound ii
Equivalent proportion with the chloro- 5,6- dicyanoquinone (DDQ) of 2,3- bis- is 1.0:1.0~1.5.
Preferably, the reaction temperature in the step (2) is 10 DEG C, reaction time 3-5h.
Preferably, the compound III generated in step (2) is purified, the purification step includes using sodium sulfite
Aqueous solution washing, extraction, it is dry, be evaporated after obtain crude product, the crude product of acquisition is used into water, ethyl alcohol, PE:EA=20:1 in order
Mashing, suction filtration obtain product.
Preferably, solvent used in phosphorus acylation reaction is methylene chloride (DCM) or tetrahydrofuran in the step (3)
(THF), catalyst used in the phosphorus acylation reaction is triethylamine or pyridine.
Preferably, the temperature that step (4) compounds Ⅳ is reacted with trimethylamine is 30 DEG C~60 DEG C, reaction time 7-
10h。
It preferably, further include purification step in the step (4), the purification step includes filtering, and will filter acquisition
Filter cake is beaten with acetonitrile.
The beneficial effects of the present invention are:
(1) present invention use simple chemical compounds I for starting material, through over-churning, the deprotection of ether, phosphorus acylation reaction with
And hydrolysis obtains i.e. bis- (18 carbon -2, the 4- dienoyl) phosphatidyl cholines of compound V, the chirality of compound in reaction
It does not change, high income, total recovery is up to Y=85.6%*83.3%*80.1%*85.7%=49%；
(2) present invention is not related to the use of expensive reagent, reduces costs；
(3) what synthesis technology of the invention was related to is easy to operate, and condition is easily-controllable, easy to industrialized production.
Detailed description of the invention
Fig. 1 is the synthetic route one of (18 carbon -2,4- dienoyl) phosphatidyl cholines bis- in the prior art；
Fig. 2 is the synthetic route two of (18 carbon -2,4- dienoyl) phosphatidyl cholines bis- in the prior art；
Fig. 3 is the synthetic route chart of bis- (the 18 carbon -2,4- dienoyl) phosphatidyl cholines of the present invention.
Specific embodiment
The present invention is described in further details below with reference to Figure of description and embodiment.
Test material and reagent as used in the following examples etc., unless otherwise specified, commercially obtain.
In the examples where no specific technique or condition is specified, can according to the literature in the art described technology or
Condition is carried out according to product description.
Embodiment 1
Compound ii: the synthesis of 2,4- octadecane dienoic acid -3- (4- mehtoxybenzyl oxygroup) -1,2- propylene diester
By 4g chemical compounds I 3- (4- mehtoxybenzyl oxygroup) -1,2- propylene glycol and it is dissolved in 40mL methylene chloride (DCM)
In, 13.21g 2 is added, 4- octadecane dienoic acid adds bis- hexamethylene of 4-dimethylaminopyridine (DMAP) and 7.78g of 2.30g
Base carbodiimide (DCC), system gradually become muddy, and reaction temperature is 15 DEG C, and thin-layer chromatography (TLC) monitors extent of reaction (second
Acetoacetic ester: petroleum ether=5:1), react 9h.It filtering after removing insoluble matter, the mother liquor of suction filtration is washed with 1M HCl, layering, and DCM layers
Washing, anhydrous sodium sulfate is dry, is evaporated to obtain colorless oil.It crosses column purification and obtains compound ii 11.9g, yield is 11.9/ (4*
737.12/212.25)=85.6%.
Wherein, the nuclear magnetic resonance data of compound ii is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.60 (dd, J=30.2,18.9Hz, 1H), 6.95 (td, J=15.1,
12.6Hz, 2H), 6.50 (ddt, J=30.2,8.6,1.9Hz, 1H), 5.72 (dt, J=30.2,12.4Hz, 1H), 5.48 (tt,
J=13.5,10.8Hz, 1H), 5.32 (d, J=30.2Hz, 1H), 4.56 (dd, J=24.9,13.6Hz, 1H), 4.46 (s,
1H), 4.18 (dd, J=24.8,13.6Hz, 1H), 3.79 (s, 1H), 3.71 (dd, J=24.7,10.8Hz, 1H), 3.39 (dd,
J=24.7,10.8Hz, 1H), 2.11-1.89 (m, 2H), 1.41-1.15 (m, 23H), 0.96-0.80 (m, 3H)
Embodiment 2
Compound ii: the synthesis of 2,4- octadecane dienoic acid -3- (4- mehtoxybenzyl oxygroup) -1,2- propylene diester
4g chemical compounds I 3- (4- mehtoxybenzyl oxygroup) -1,2-PD is dissolved in 40mL DCM, is added
13.21g2,4- octadecane dienoic acid add DMAP and 7.23g 1- (3- the dimethylamino-propyl) -3- ethyl carbon two of 2.30g
Inferior amine salt hydrochlorate (EDCI), system gradually become muddy, and reaction temperature is 15 DEG C, and thin-layer chromatography (TLC) monitors extent of reaction (second
Acetoacetic ester: petroleum ether=5:1), react 9h.It filters and removes insoluble matter.The mother liquor of suction filtration is washed with 1M HCl, layering, DCM layers of water
It washes, anhydrous sodium sulfate is dry, is evaporated to obtain colorless oil.It crosses column purification and obtains compound ii 11.3g, yield is 11.3/ (4*
737.12/212.25)=81.2%.
Wherein, the nuclear magnetic resonance data of compound ii is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.60 (dd, J=30.2,18.9Hz, 1H), 6.95 (td, J=15.1,
12.6Hz, 2H), 6.50 (ddt, J=30.2,8.6,1.9Hz, 1H), 5.72 (dt, J=30.2,12.4Hz, 1H), 5.48 (tt,
J=13.5,10.8Hz, 1H), 5.32 (d, J=30.2Hz, 1H), 4.56 (dd, J=24.9,13.6Hz, 1H), 4.46 (s,
1H), 4.18 (dd, J=24.8,13.6Hz, 1H), 3.79 (s, 1H), 3.71 (dd, J=24.7,10.8Hz, 1H), 3.39 (dd,
J=24.7,10.8Hz, 1H), 2.11-1.89 (m, 2H), 1.41-1.15 (m, 23H), 0.96-0.80 (m, 3H)
Embodiment 3
Compound ii: the synthesis of 2,4- octadecane dienoic acid -3- (4- mehtoxybenzyl oxygroup) -1,2- propylene diester
4g chemical compounds I 3- (4- mehtoxybenzyl oxygroup) -1,2-PD is dissolved in 40mL DCM, 13.21g is added
2,4- octadecane dienoic acids add DMAP the and 9.72g DCC of 2.30g, and system gradually becomes muddy, reaction temperature 30
DEG C, thin-layer chromatography (TLC) monitors extent of reaction (ethyl acetate: petroleum ether=5:1), reacts 7h.It filters and removes insoluble matter.It filters
Mother liquor washed with 1M HCl, be layered, DCM layer washing, anhydrous sodium sulfate dry, be evaporated to obtain colorless oil.Column purification is crossed to obtain
Compound ii 11.8g, yield are 11.8/ (4*737.12/212.25)=84.9%.
Wherein, the nuclear magnetic resonance data of compound ii is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.60 (dd, J=30.2,18.9Hz, 1H), 6.95 (td, J=15.1,
12.6Hz, 2H), 6.50 (ddt, J=30.2,8.6,1.9Hz, 1H), 5.72 (dt, J=30.2,12.4Hz, 1H), 5.48 (tt,
J=13.5,10.8Hz, 1H), 5.32 (d, J=30.2Hz, 1H), 4.56 (dd, J=24.9,13.6Hz, 1H), 4.46 (s,
1H), 4.18 (dd, J=24.8,13.6Hz, 1H), 3.79 (s, 1H), 3.71 (dd, J=24.7,10.8Hz, 1H), 3.39 (dd,
J=24.7,10.8Hz, 1H), 2.11-1.89 (m, 2H), 1.41-1.15 (m, 23H), 0.96-0.80 (m, 3H)
Embodiment 4
Compound III: the synthesis of 2,4- octadecane dienoic acid -3- (4- mehtoxybenzyl oxygroup) -1,2- glycerine
10g compound ii is dissolved in 50mL DCM, 3.08gDDQ is added, adds the water of 2mL, reaction temperature 10
DEG C, after reacting 3h, product is washed with sodium sulfite aqueous solution, it is dry, it is evaporated, the crude product of acquisition successively uses water, ethyl alcohol, poly- second
Alkene: ethyl acetate (PE:EA)=20:1 mashing filters, and obtains white solid 6.46g, and yield is 6.46/ (10*616.97/
737.12)=76.9%.
Wherein, the nuclear magnetic resonance data of compound III is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.41-7.21 (m, 1H), 6.19 (dd, J=7.2,3.2Hz, 1H), 5.83 (dd,
J=15.3,9.9Hz, 1H), 5.23-5.09 (m, 1H), 4.41 (d, J=5.1Hz, 1H), 3.80 (d, J=4.6Hz, 1H),
2.19 (dd, J=11.9,6.8Hz, 1H), 1.51-1.39 (m, 1H), 1.29 (d, J=7.9Hz, 8H), 0.90 (t, J=
6.9Hz,1H).
Embodiment 5
Compound III: the synthesis of 2,4- octadecane dienoic acid -3- (4- mehtoxybenzyl oxygroup) -1,2- glycerine
10g compound ii is dissolved in 50mL DCM, 3.70g DDQ is added, adds the water of 2mL, reaction temperature 10
DEG C, react 3h.Product is washed with sodium sulfite aqueous solution, it is dry, it is evaporated, the crude product of acquisition successively uses water, ethyl alcohol, PE:EA
=20:1 mashing, filters, and obtains white solid 7.0g, and yield is 7.0/ (10*616.97/737.12)=83.3%.
Wherein, the nuclear magnetic resonance data of compound III is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.41-7.21 (m, 1H), 6.19 (dd, J=7.2,3.2Hz, 1H), 5.83 (dd,
J=15.3,9.9Hz, 1H), 5.23-5.09 (m, 1H), 4.41 (d, J=5.1Hz, 1H), 3.80 (d, J=4.6Hz, 1H),
2.19 (dd, J=11.9,6.8Hz, 1H), 1.51-1.39 (m, 1H), 1.29 (d, J=7.9Hz, 8H), 0.90 (t, J=
6.9Hz,1H).
Embodiment 6
Compound III: the synthesis of 2,4- octadecane dienoic acid -3- (4- mehtoxybenzyl oxygroup) -1,2- glycerine
10g compound ii is dissolved in 50mL DCM, 4.62g DDQ is added, adds the water of 2mL, reaction temperature 10
DEG C, react 3h.Product is washed with sodium sulfite aqueous solution, it is dry, it is evaporated；The crude product of acquisition successively uses water, ethyl alcohol, PE:EA
=20:1 mashing, filters, and obtains white solid 6.57g, and yield is 6.57/ (10*616.97/737.12)=78.2%.
Wherein, the nuclear magnetic resonance data of compound III is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.41-7.21 (m, 1H), 6.19 (dd, J=7.2,3.2Hz, 1H), 5.83 (dd,
J=15.3,9.9Hz, 1H), 5.23-5.09 (m, 1H), 4.41 (d, J=5.1Hz, 1H), 3.80 (d, J=4.6Hz, 1H),
2.19 (dd, J=11.9,6.8Hz, 1H), 1.51-1.39 (m, 1H), 1.29 (d, J=7.9Hz, 8H), 0.90 (t, J=
6.9Hz,1H).
Embodiment 7
Compounds Ⅳ: the synthesis of bis- (18 carbon -2,4- dienoyl) phosphoric acid bromine ethyl esters
In the 50mL three-necked bottle equipped with magnetic agitation, 5g (mol) compound III is dissolved in the dry THF of 20mL, is added
Enter 1.64g triethylamine.3.92g B- bromoethyl phosphinylidyne dichloro is added dropwise under ice-water bath.15 DEG C of reaction 2h.Sample TLC detection, raw material
After reaction, 15mL saturated sodium bicarbonate solution is added, so that compound is formed sodium salt, is stirred overnight.Sampling TLC inspection every other day
It surveys, after product generates, is washed with 1MHCl, extracted, liquid separation, water phase is extracted with DCM, merges organic phase.Saturated sodium chloride solution is washed
It washs, anhydrous sodium sulfate drying at room temperature 10min is added, is evaporated, silica gel column chromatography obtains 5.28g colorless oil, yield 5.28/
(5*802.89/616.97)=78.8%.
Wherein, the nuclear magnetic resonance data of compound III is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.55 (dd, J=30.2,12.3Hz, 1H), 6.47 (ddt, J=41.0,30.2,
1.8Hz, 1H), 5.80-5.57 (m, 2H), 5.35 (s, 1H), 5.29 (s, 1H), 4.70-4.46 (m, 2H), 4.38 (ddd, J=
25.3,17.0,8.4Hz, 1H), 4.24-4.05 (m, 1H), 3.74 (t, J=14.8Hz, 1H), 2.08-1.95 (m, 2H),
1.37–1.18(m,23H),0.96–0.83(m,3H).
Embodiment 8
Compounds Ⅳ: the synthesis of bis- (18 carbon -2,4- dienoyl) phosphoric acid bromine ethyl esters
In the 50mL three-necked bottle equipped with magnetic agitation, 5g compound III is dissolved in the THF of the drying of 20mL, is added
1.28g pyridine.3.92gB- bromoethyl phosphinylidyne dichloro is added dropwise under ice-water bath.15 DEG C of reaction 2h, sampling TLC detection, raw material reaction knot
15mL saturated sodium bicarbonate solution is added in Shu Hou, so that compound is formed sodium salt, is stirred overnight.Sampling TLC detection every other day, product
It after generation, is washed, is extracted with 1MHCl, liquid separation, water phase is extracted with DCM, merges organic phase.Saturated sodium chloride solution washing, is added
Anhydrous sodium sulfate drying at room temperature 10min, is evaporated, and silica gel column chromatography obtains 5.17g colorless oil, and yield is 5.17/ (5*
802.89/616.97)=77.3%.
Wherein, the nuclear magnetic resonance data of compounds Ⅳ is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.55 (dd, J=30.2,12.3Hz, 1H), 6.47 (ddt, J=41.0,30.2,
1.8Hz, 1H), 5.80-5.57 (m, 2H), 5.35 (s, 1H), 5.29 (s, 1H), 4.70-4.46 (m, 2H), 4.38 (ddd, J=
25.3,17.0,8.4Hz, 1H), 4.24-4.05 (m, 1H), 3.74 (t, J=14.8Hz, 1H), 2.08-1.95 (m, 2H),
1.37–1.18(m,23H),0.96–0.83(m,3H).
Embodiment 9
Compounds Ⅳ: the synthesis of bis- (18 carbon -2,4- dienoyl) phosphoric acid bromine ethyl esters
In the 50ml three-necked bottle equipped with magnetic agitation, 5g compound III is dissolved in the DCM of 20ml, 1.28g pyrrole is added
Pyridine.3.92g B- bromoethyl phosphinylidyne dichloro is added dropwise under ice-water bath.15 DEG C of reaction 2h.Sample TLC detection, raw material after reaction,
15mL saturated sodium bicarbonate solution is added, so that compound is formed sodium salt, is stirred overnight.Sampling TLC detection, product generate every other day
Afterwards, it is washed, is extracted with 1MHCl, liquid separation, water phase is extracted with DCM, merges organic phase.Saturated sodium chloride solution washing, is added anhydrous
Sodium sulphate drying at room temperature 10min, is evaporated, and silica gel column chromatography obtains 5.36g colorless oil, and yield is 5.36/ (5*802.89/
616.97)=80.1%.
Wherein, the nuclear magnetic resonance data of compounds Ⅳ is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.55 (dd, J=30.2,12.3Hz, 1H), 6.47 (ddt, J=41.0,30.2,
1.8Hz, 1H), 5.80-5.57 (m, 2H), 5.35 (s, 1H), 5.29 (s, 1H), 4.70-4.46 (m, 2H), 4.38 (ddd, J=
25.3,17.0,8.4Hz, 1H), 4.24-4.05 (m, 1H), 3.74 (t, J=14.8Hz, 1H), 2.08-1.95 (m, 2H),
1.37–1.18(m,23H),0.96–0.83(m,3H).
Embodiment 10
Compound V: the synthesis of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines
5g compounds Ⅳ is transferred in pressure bottle, excessively dry front three amine gas, sealed pressure are passed through into system
Bottle, it after reacting 10h at 30 DEG C, filters, filter cake is beaten with acetonitrile, obtains white waxy solid 4.01g, and yield is 4.01/ (5*
802.89/616.97)=82.1%.
Wherein, the nuclear magnetic resonance data of compounds Ⅳ is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.60 (dd, J=30.2,18.9Hz, 1H), 6.95 (td, J=15.1,
12.6Hz, 2H), 6.50 (ddt, J=30.2,8.6,1.9Hz, 1H), 5.72 (dt, J=30.2,12.4Hz, 1H), 5.48 (tt,
J=13.5,10.8Hz, 1H), 5.32 (d, J=30.2Hz, 1H), 4.56 (dd, J=24.9,13.6Hz, 1H), 4.46 (s,
1H), 4.18 (dd, J=24.8,13.6Hz, 1H), 3.79 (s, 1H), 3.71 (dd, J=24.7,10.8Hz, 1H), 3.39 (dd,
J=24.7,10.8Hz, 1H), 2.11-1.89 (m, 2H), 1.41-1.15 (m, 23H), 0.96-0.80 (m, 3H)
Embodiment 11
Compound V: the synthesis of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines
5g compounds Ⅳ is transferred in pressure bottle, excessively dry front three amine gas, sealed pressure are passed through into system
Bottle, it after reacting 8h at 40 DEG C, filters, filter cake is beaten with acetonitrile, obtains white waxy solid 4.17g, and yield is 4.17/ (5*
782.10/802.89)=85.7%.
Wherein, the nuclear magnetic resonance data of compounds Ⅳ is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.60 (dd, J=30.2,18.9Hz, 1H), 6.95 (td, J=15.1,
12.6Hz, 2H), 6.50 (ddt, J=30.2,8.6,1.9Hz, 1H), 5.72 (dt, J=30.2,12.4Hz, 1H), 5.48 (tt,
J=13.5,10.8Hz, 1H), 5.32 (d, J=30.2Hz, 1H), 4.56 (dd, J=24.9,13.6Hz, 1H), 4.46 (s,
1H), 4.18 (dd, J=24.8,13.6Hz, 1H), 3.79 (s, 1H), 3.71 (dd, J=24.7,10.8Hz, 1H), 3.39 (dd,
J=24.7,10.8Hz, 1H), 2.11-1.89 (m, 2H), 1.41-1.15 (m, 23H), 0.96-0.80 (m, 3H)
Embodiment 12
Compound V: the synthesis of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines
5g compounds Ⅳ is transferred in pressure bottle, excessively dry front three amine gas, sealed pressure are passed through into system
Bottle, it after reacting 8h at 60 DEG C, filters, filter cake is beaten with acetonitrile, obtains white waxy solid 4.10g, and yield is 4.10/ (5*
782.10/802.89)=84.2%.
Wherein, the nuclear magnetic resonance data of compounds Ⅳ is as follows, determines compound structure according to the ownership of hydrogen atom:
1H NMR(500MHz,CDCl3) δ 7.60 (dd, J=30.2,18.9Hz, 1H), 6.95 (td, J=15.1,
12.6Hz, 2H), 6.50 (ddt, J=30.2,8.6,1.9Hz, 1H), 5.72 (dt, J=30.2,12.4Hz, 1H), 5.48 (tt,
J=13.5,10.8Hz, 1H), 5.32 (d, J=30.2Hz, 1H), 4.56 (dd, J=24.9,13.6Hz, 1H), 4.46 (s,
1H), 4.18 (dd, J=24.8,13.6Hz, 1H), 3.79 (s, 1H), 3.71 (dd, J=24.7,10.8Hz, 1H), 3.39 (dd,
J=24.7,10.8Hz, 1H), 2.11-1.89 (m, 2H), 1.41-1.15 (m, 23H), 0.96-0.80 (m, 3H)
In conclusion the parameter in synthesis technology be it is best, in esterification, 2,4- octadecane dienoic acids cannot be lower than
2.0, the by-product of mono-esterification otherwise can be generated, yield is reduced；If excessive be added, then unreacted 2,4- ten is not only removed
Eight alkane dienoic acids also result in cost raising；Room temperature can reach reaction condition in deprotection reaction, and improving reaction temperature can be with
Shorten the reaction time；Higher using the yield of organic base pyridine in phosphonylation reaction, for triethylamine as inorganic base, yield is slightly lower；
In hydrolysis, trimethylamine be it is excessive, due to its be gas, so to guarantee reaction airtightness, and can be used pH test paper
To judge whether trimethylamine is enough.The synthetic method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines of the invention has
Advantage at low cost, yield is high, easy to industrialized production.
The above is only the preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-described embodiment,
It is within the scope of the invention with present inventive concept without the various process programs of substantial differences.
Claims (10)
1. a kind of preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines, it is characterised in that: including following step
It is rapid:
(1) by chemical compounds I, i.e. 3- (4- mehtoxybenzyl oxygroup) -1,2-PD and 2,4- octadecane dienoic acid generation ester
Change reaction and generates compound ii；
(2) compound ii and 2 that will be synthesized in step (1), chloro- 5, the 6- dicyanoquinone of 3- bis- mixing, occurs the deprotection of ether
Reaction generates compound III；
(3) phosphorus acylation reaction is occurred into for the compound III and B- bromoethyl phosphinylidyne dichloro that synthesize in step (2) and generates compounds Ⅳ；
(4) after hydrolysis being occurred for the compounds Ⅳ and front three amine gas that synthesize in step (3), final product V is generated, i.e.,
Bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines.
2. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 1, feature exist
In: solvent used in the esterification reaction process of the step (1) includes methylene chloride, used in the esterification reaction process
Condensing agent is dicyclohexylcarbodiimide or 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride；The esterification is anti-
Answering catalyst used in process is 4-dimethylaminopyridine.
3. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 2, feature exist
In: the molar ratio of step (1) chemical compounds I and condensing agent is 2:2.5.
4. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 1, feature exist
In: the reaction temperature in the step (1) is 10-20 DEG C, reaction time 7-9h.
5. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 1, feature exist
In: the compound ii generated in step (1) is purified, the purification step includes suction filtration, acidification, extraction, dry, steaming
It is dry.
6. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 1, feature exist
In: the solvent that deprotection reaction uses in the step (2) is methylene chloride, the compound ii and 2, chloro- 5, the 6- bis- of 3- bis-
The equivalent proportion of cyanogen 1,4-benzoquinone is 1.0:1.0~1.5.
7. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 1, feature exist
In: the reaction temperature in the step (2) is 10 DEG C, reaction time 3-5h.
8. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 1, feature exist
In: the compound III generated in step (2) is purified, the purification step include using sodium sulfite aqueous solution washing,
Extraction, drying obtain crude product after being evaporated, and use water, ethyl alcohol, PE:EA=20:1 to be beaten in order the crude product of acquisition.
9. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 1, feature exist
In: solvent used in phosphorus acylation reaction is methylene chloride or tetrahydrofuran in the step (3), is made in the phosphorus acylation reaction
Catalyst is triethylamine or pyridine.
10. the preparation method of bis- (18 carbon -2,4- dienoyl) phosphatidyl cholines according to claim 1, feature
Be: the temperature that compounds Ⅳ is reacted with trimethylamine in the step (4) is 30 DEG C~60 DEG C, reaction time 7-10h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59179128A (en) * | 1983-03-31 | 1984-10-11 | Hidetoshi Tsuchida | Oxygen adsorbing and desorbing agent |
| WO2015128488A1 (en) * | 2014-02-27 | 2015-09-03 | Ratiopharm Gmbh | Derivatives of polyhydroxy compounds |
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2019
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59179128A (en) * | 1983-03-31 | 1984-10-11 | Hidetoshi Tsuchida | Oxygen adsorbing and desorbing agent |
| WO2015128488A1 (en) * | 2014-02-27 | 2015-09-03 | Ratiopharm Gmbh | Derivatives of polyhydroxy compounds |
Non-Patent Citations (2)
| Title |
|---|
| MASAMI ISHIHARA 等: "Facile and Useful Synthesis of Enantiomeric Phosphatidylcholines", 《CHEM. PHARM. BULL.》 * |
| RICHARD M. EPAND 等: "Substrate Chirality and Specificity of Diacylglycerol Kinases and the Multisubstrate Lipid Kinase", 《BIOCHEMISTRY》 * |
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