CN110128468B - Synthesis method of bis (octadeca-2, 4-dienoyl) phosphatidylcholine - Google Patents
Synthesis method of bis (octadeca-2, 4-dienoyl) phosphatidylcholine Download PDFInfo
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- CN110128468B CN110128468B CN201910531430.9A CN201910531430A CN110128468B CN 110128468 B CN110128468 B CN 110128468B CN 201910531430 A CN201910531430 A CN 201910531430A CN 110128468 B CN110128468 B CN 110128468B
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- -1 octadeca-2, 4-dienoyl Chemical group 0.000 title claims abstract description 46
- 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 title claims abstract description 33
- 238000001308 synthesis method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims abstract description 20
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 19
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 19
- 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 14
- 238000005886 esterification reaction Methods 0.000 claims abstract description 12
- ADHNUPOJJCKWRT-JLXBFWJWSA-N (2e,4e)-octadeca-2,4-dienoic acid Chemical compound CCCCCCCCCCCCC\C=C\C=C\C(O)=O ADHNUPOJJCKWRT-JLXBFWJWSA-N 0.000 claims abstract description 8
- ADHNUPOJJCKWRT-UHFFFAOYSA-N 2,4-octadecadienoic acid Natural products CCCCCCCCCCCCCC=CC=CC(O)=O ADHNUPOJJCKWRT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- MFKMOLJNQHPVHC-UHFFFAOYSA-N 3-[(4-methoxyphenyl)methoxy]propane-1,2-diol Chemical compound COC1=CC=C(COCC(O)CO)C=C1 MFKMOLJNQHPVHC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 30
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- 238000000967 suction filtration Methods 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 7
- 239000004698 Polyethylene Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- 238000006366 phosphorylation reaction Methods 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 9
- 238000010009 beating Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 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 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000007789 gas Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- IAQNLUJLASSNLX-UHFFFAOYSA-N 2-bromoethyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCBr IAQNLUJLASSNLX-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
- 239000012230 colorless oil Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 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
- 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
- 239000003012 bilayer membrane Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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
- USWYUNFYMUKUNS-SRUCOHQKSA-N [(2r)-2,3-bis[10-[(2e,4e)-hexa-2,4-dienoyl]oxydecanoyloxy]propyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound C\C=C\C=C\C(=O)OCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCOC(=O)\C=C\C=C\C USWYUNFYMUKUNS-SRUCOHQKSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000001514 detection method 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
- 230000032050 esterification Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 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
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000005954 phosphonylation reaction Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- 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
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- 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 invention discloses a preparation method of bis (octadeca-2, 4-dienoyl) phosphatidylcholine, which relates to the field of compound preparation and comprises the following steps: (1) carrying out esterification reaction on a compound I, namely 3- (4-methoxy benzyl oxy) -1, 2-propylene glycol and 2, 4-octadecadienoic acid to generate a compound II; (2) mixing the compound II synthesized in the step (1) with 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ) to generate a compound III; (3) reacting the compound III synthesized in the step (2) with B-bromoethyl phosphoryl dichloride to generate a compound IV; (4) and (3) reacting the compound IV synthesized in the step (3) with trimethylamine gas, and introducing a solvent to react to generate the bis (octadeca-2, 4-dienoyl) phosphatidylcholine. The invention has the beneficial effects that: high yield (49% total yield) and low cost.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation method of bis (octadeca-2, 4-dienoyl) phosphatidylcholine.
Background
Bis (octadeca-2, 4-dienoyl) phosphatidylcholine, Bis-dienylphosphatidylcholine for short, is a class of dienoyl phospholipids that has received much attention as carriers for drug delivery systems and can be used to encapsulate drugs, such as anticancer agents, proteins and other biologically active substances. In addition, the bis (octadeca-2, 4-dienoyl) phosphatidylcholine is easy to form a poly (lipid) vesicle and a plane-supported bilayer, the stability of a surfactant, a solvent and long-term storage can be obviously improved, the phospholipid can be subjected to cross-linking polymerization, the stability of a membrane can be obviously enhanced compared with linear polymerization, and the permeability of ions and small molecules can be changed. Therefore, the development of a preparation method which is economical and practical and is simple and convenient to operate has very important significance and value.
The synthesis of phosphatidylcholine intermediates has been reported in the relevant literature. Two synthetic routes to bis (octadeca-2, 4-dienoyl) phosphatidylcholine are reported in the literature. The document JPNES, I.W.and HALL Jr. H.K. modification of a conversion of a generated a p-roach to UV-polymerizable lipids bis DenPC and bis SorbPC [ J ]. Tetrahedron Letters,2011,52, 3699-.
The two routes described in the publications HEITZ B.A., JONES I.W., HALL H.K., et al.sectional polymerization of a suspended planar Bilayer Membranes a fluid, high hly stable membrane for ion channel recordings [ J ]. J.AM.CHEM.SOC.,2010,132, 7086. and Dorn K.Klingbiel R.T., Specht D.P. Permeability channels of Polymeric Bilayer Membranes from Methacryloyloxy and Butadiene Lipids [ J.AM.SOC., 1984,106, 1627. Zones 1633 are shown in FIG. 2, starting with compound (1) and condensing with glycerol anhydride (4) and then with phosphatidylcholine (DCC 3). In this scheme, the yield of the compound (4) synthesized is only 25%, and one molecule of the compound (1) is lost in the condensation with GPC, which is poor in atomic economy, low in yield, and high in cost.
Disclosure of Invention
The invention solves the technical problems of low yield and high cost of the existing synthetic method of the bis (octadeca-2, 4-dienoyl) phosphatidylcholine.
As shown in FIG. 3, FIG. 3 is a synthetic scheme of bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to the present invention.
The invention adopts the following technical scheme to solve the technical problems:
the invention provides a preparation method of bis (octadeca-2, 4-dienoyl) phosphatidylcholine, which comprises the following steps:
(1) carrying out esterification reaction on a compound I, namely 3- (4-methoxy benzyl oxy) -1, 2-propylene glycol and 2, 4-octadecadienoic acid to generate a compound II;
(2) mixing the compound II synthesized in the step (1) with 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ) to carry out ether deprotection reaction to generate a compound III;
(3) carrying out phosphorylation reaction on the compound III synthesized in the step (2) and B-bromoethyl phosphoryl dichloride to generate a compound IV;
(4) and (3) carrying out hydrolysis reaction on the compound IV synthesized in the step (3) and trimethylamine gas to generate a final product V, namely bis (octadeca-2, 4-dienoyl) phosphatidylcholine.
Preferably, the solvent used during the esterification reaction of step (1) comprises Dichloromethane (DCM), and the condensing agent used during the esterification reaction is Dicyclohexylcarbodiimide (DCC) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI); the catalyst used in the esterification reaction process is 4-Dimethylaminopyridine (DMAP).
Preferably, the molar ratio of the compound I to the condensing agent in the step (1) is 2: 2.5.
Preferably, the reaction temperature in the step (1) is 10-20 ℃, and the reaction time is 7-9 h.
Preferably, the compound II generated in the step (1) is purified, and the purification step comprises suction filtration, acidification, extraction, drying and evaporation to dryness.
Preferably, the solvent used in the deprotection reaction in the step (2) is Dichloromethane (DCM), and the equivalent ratio of the compound II to 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (DDQ) is 1.0: 1.0-1.5.
Preferably, the reaction temperature in the step (2) is 10 ℃, and the reaction time is 3-5 h.
Preferably, the compound iii produced in step (2) is purified, and the purification step comprises washing with an aqueous solution of sodium sulfite, extracting, drying, and evaporating to obtain a crude product, and the crude product is obtained by sequentially using water, ethanol, and PE: EA ═ 20: pulping, and performing suction filtration to obtain a product.
Preferably, the solvent used in the phosphorylation reaction in the step (3) is Dichloromethane (DCM) or Tetrahydrofuran (THF), and the catalyst used in the phosphorylation reaction is triethylamine or pyridine.
Preferably, the reaction temperature of the compound IV in the step (4) and trimethylamine is 30-60 ℃, and the reaction time is 7-10 h.
Preferably, the step (4) further comprises a purification step, wherein the purification step comprises suction filtration, and a filter cake obtained by suction filtration is pulped with acetonitrile.
The invention has the beneficial effects that:
(1) the invention adopts simple compound I as an initial raw material, and obtains compound V, namely bis (octadeca-2, 4-dienoyl) phosphatidylcholine through esterification, ether deprotection, phosphorylation reaction and hydrolysis reaction, the chirality of the compound is not changed in the reaction, the yield is high, and the total yield can reach 85.6 percent by 83.3 percent by 80.1 percent by 85.7 percent by 49 percent;
(2) the invention does not relate to the use of expensive reagents, thus reducing the cost;
(3) the synthesis process of the invention has simple operation, easily controlled conditions and easy industrial production.
Drawings
FIG. 1 is a first scheme for the synthesis of bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to the prior art;
FIG. 2 is a second scheme of the synthesis of bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to the prior art;
FIG. 3 is a scheme showing the synthesis scheme of bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to the present invention.
Detailed Description
The invention will be described in further detail below with reference to the drawings and examples of the specification.
Test materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The specific techniques or conditions not specified in the examples can be performed according to the techniques or conditions described in the literature in the field or according to the product specification.
Example 1
Compound ii: synthesis of 2, 4-octadecadienoic acid-3- (4-methoxybenzyloxy) -1, 2-propylene diester
4g of the compound I3- (4-methoxyphenylmethyloxy) -1, 2-propanediol was dissolved in 40mL of Dichloromethane (DCM) and 13.21g of 2, 4-octadecadienoic acid was added, and then 2.30g of 4-Dimethylaminopyridine (DMAP) and 7.78g of Dicyclohexylcarbodiimide (DCC) were added, the system gradually became cloudy at a reaction temperature of 15 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) (ethyl acetate: petroleum ether ═ 5: 1) and reacted for 9 hours. After removing insoluble substances by suction filtration, the mother liquor obtained by suction filtration is washed by 1M HCl, separated, washed by DCM layer, dried by anhydrous sodium sulfate and evaporated to dryness to obtain colorless oily substance. The compound II was purified by column chromatography in 11.9g yield (11.9/(4 × 737.12/212.25) ═ 85.6%.
Wherein, the nuclear magnetic resonance data of the compound II is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.60(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＝24.7,1 0.8Hz,1H),3.39(dd,J＝24.7,10.8Hz,1H),2.11-1.89(m,2H),1.41–1.15(m,23 H),0.96–0.80(m,3H).
example 2
Compound ii: synthesis of 2, 4-octadecadienoic acid-3- (4-methoxybenzyloxy) -1, 2-propylene diester
4g of the compound I3- (4-methoxyphenylmethyloxy) -1, 2-propanediol was dissolved in 40mL of DCM, 13.21g of 2, 4-octadecadienoic acid was added, 2.30g of DMAP and 7.23g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) were further added, the system gradually became cloudy at a reaction temperature of 15 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) (ethyl acetate: petroleum ether ═ 5: 1) and reacted for 9 h. Insoluble matter was removed by suction filtration. The mother liquor after suction filtration is washed by 1M HCl, separated, washed by DCM layer, dried by anhydrous sodium sulfate and evaporated to dryness to obtain colorless oily matter. The compound II was purified by column chromatography in 11.3g (yield 11.3/(4 × 737.12/212.25) ═ 81.2%.
Wherein, the nuclear magnetic resonance data of the compound II is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.60(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＝24.7,1 0.8Hz,1H),3.39(dd,J＝24.7,10.8Hz,1H),2.11-1.89(m,2H),1.41–1.15(m,23 H),0.96–0.80(m,3H).
example 3
Compound ii: synthesis of 2, 4-octadecadienoic acid-3- (4-methoxybenzyloxy) -1, 2-propylene diester
4g of the compound I3- (4-methoxybenzyloxyl) -1, 2-propanediol was dissolved in 40mL of DCM, 13.21g of 2, 4-octadecadienoic acid was added, 2.30g of DMAP and 9.72g of DCC were further added, the system gradually became cloudy, the reaction temperature was 30 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) (ethyl acetate: petroleum ether: 5: 1) and reacted for 7 hours. Insoluble matter was removed by suction filtration. The mother liquor after suction filtration is washed by 1M HCl, separated, washed by DCM layer, dried by anhydrous sodium sulfate and evaporated to dryness to obtain colorless oily matter. The compound II was purified by column chromatography in 11.8g yield of 11.8/(4 × 737.12/212.25) ═ 84.9%.
Wherein, the nuclear magnetic resonance data of the compound II is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.60(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＝24.7,1 0.8Hz,1H),3.39(dd,J＝24.7,10.8Hz,1H),2.11-1.89(m,2H),1.41–1.15(m,23 H),0.96–0.80(m,3H).
example 4
Compound iii: synthesis of 2, 4-octadecadienoic acid-3- (4-methoxy benzyl oxy) -1, 2-propanetriol
Dissolving 10g of compound II in 50mL of DCM, adding 3.08g of DDQ, adding 2mL of water, reacting at 10 ℃ for 3 hours, washing a product with a sodium sulfite aqueous solution, drying, evaporating to dryness, and sequentially using water, ethanol and polyethylene as a crude product: ethyl acetate (PE: EA) ═ 20: pulping, and filtering to obtain 6.46g of white solid with yield of 6.46/(10 × 616.97/737.12) ═ 76.9%.
Wherein, the nuclear magnetic resonance data of the compound III is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.41–7.21(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).
example 5
Compound iii: synthesis of 2, 4-octadecadienoic acid-3- (4-methoxy benzyl oxy) -1, 2-propanetriol
10g of compound II was dissolved in 50mL of DCM, 3.70g of DDQ was added, and 2mL of water was further added, and the reaction temperature was 10 ℃ and the reaction was carried out for 3 hours. Washing the product with sodium sulfite aqueous solution, drying and evaporating to dryness, and sequentially using water, ethanol and PE (polyethylene) with EA being 20: pulping, and filtering to obtain 7.0g of white solid with the yield of 7.0/(10 × 616.97/737.12) ═ 83.3%.
Wherein, the nuclear magnetic resonance data of the compound III is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.41–7.21(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).
example 6
Compound iii: synthesis of 2, 4-octadecadienoic acid-3- (4-methoxy benzyl oxy) -1, 2-propanetriol
10g of compound II are dissolved in 50mL of DCM, 4.62g of DDQ are added, and 2mL of water are added, the reaction temperature is 10 ℃ and the reaction is carried out for 3 h. Washing the product with sodium sulfite aqueous solution, drying and evaporating to dryness; the crude product obtained is successively extracted with water, ethanol, PE, EA 20: pulping, and filtering to obtain 6.57g of white solid with yield of 6.57/(10 × 616.97/737.12) ═ 78.2%.
Wherein, the nuclear magnetic resonance data of the compound III is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.41–7.21(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).
example 7
A compound IV: synthesis of bis (octadecyl-2, 4-dienoyl) bromoethyl phosphate
In a 50mL three-necked flask with magnetic stirring, 5g of (mol) compound III are dissolved in 20mL of dry THF, and 1.64g of triethylamine are added. 3.92g B-bromoethyl phosphoryl dichloride was added dropwise in an ice water bath. Reacting at 15 ℃ for 2 h. TLC sampling was performed, and after the reaction of the starting materials was completed, 15mL of saturated sodium bicarbonate solution was added to allow the compound to form a sodium salt, which was stirred overnight. TLC sampling is carried out every other day to detect, after the product is generated, the product is washed by 1MHCl, extracted, separated, the water phase is extracted by DCM, and the organic phases are combined. The extract was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate at room temperature for 10min, evaporated to dryness, and subjected to silica gel column chromatography to give 5.28g of a colorless oil, with a yield of 5.28/(5 × 802.89/616.97) ═ 78.8%.
Wherein, the nuclear magnetic resonance data of the compound III is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.55(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＝14.8 Hz,1H),2.08–1.95(m,2H),1.37–1.18(m,23H),0.96–0.83(m,3H).
example 8
A compound IV: synthesis of bis (octadecyl-2, 4-dienoyl) bromoethyl phosphate
In a 50mL three-necked flask equipped with magnetic stirring, 5g of Compound III were dissolved in 20mL of dry THF, and 1.28g of pyridine was added. 3.92g of B-bromoethyl phosphoryl dichloride was added dropwise in an ice-water bath. After the reaction at 15 ℃ for 2h and sampling for TLC detection, 15mL of saturated sodium bicarbonate solution was added to allow the compound to form sodium salt, and the mixture was stirred overnight. TLC sampling is carried out every other day to detect, after the product is generated, the product is washed by 1MHCl, extracted, separated, the water phase is extracted by DCM, and the organic phases are combined. The extract was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate at room temperature for 10min, evaporated to dryness, and subjected to silica gel column chromatography to give 5.17g of a colorless oil at a yield of 5.17/(5 × 802.89/616.97) ═ 77.3%.
Wherein, the nuclear magnetic resonance data of the compound IV is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.55(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＝14.8 Hz,1H),2.08–1.95(m,2H),1.37–1.18(m,23H),0.96–0.83(m,3H).
example 9
A compound IV: synthesis of bis (octadecyl-2, 4-dienoyl) bromoethyl phosphate
In a 50ml three-necked flask equipped with magnetic stirring, 5g of compound III are dissolved in 20ml of DCM, and 1.28g of pyridine are added. 3.92g B-bromoethyl phosphoryl dichloride was added dropwise in an ice water bath. Reacting at 15 ℃ for 2 h. TLC sampling was performed, and after the reaction of the starting materials was completed, 15mL of saturated sodium bicarbonate solution was added to allow the compound to form a sodium salt, which was stirred overnight. TLC sampling is carried out every other day to detect, after the product is generated, the product is washed by 1MHCl, extracted, separated, the water phase is extracted by DCM, and the organic phases are combined. The extract was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate at room temperature for 10min, evaporated to dryness, and subjected to silica gel column chromatography to give 5.36g of a colorless oil at a yield of 5.36/(5 × 802.89/616.97) ═ 80.1%.
Wherein, the nuclear magnetic resonance data of the compound IV is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.55(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＝14.8 Hz,1H),2.08–1.95(m,2H),1.37–1.18(m,23H),0.96–0.83(m,3H).
example 10
Compound v: synthesis of bis (octadeca-2, 4-dienoyl) phosphatidylcholine
5g of compound IV was transferred to a pressure bottle, an excess amount of dry trimethylamine gas was introduced into the system, the pressure bottle was sealed, the reaction was carried out at 30 ℃ for 10 hours, the reaction was carried out by suction filtration, and the filter cake was slurried with acetonitrile to obtain 4.01g of a white waxy solid at a yield of 4.01/(5 × 802.89/616.97) ═ 82.1%.
Wherein, the nuclear magnetic resonance data of the compound IV is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.60(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).
example 11
Compound v: synthesis of bis (octadeca-2, 4-dienoyl) phosphatidylcholine
5g of compound IV was transferred to a pressure bottle, excess dry trimethylamine gas was introduced into the system, the pressure bottle was sealed, the reaction was carried out at 40 ℃ for 8 hours, the reaction was carried out by suction filtration, and the filter cake was slurried with acetonitrile to obtain 4.17g of a white waxy solid at a yield of 4.17/(5 × 782.10/802.89) ═ 85.7%.
Wherein, the nuclear magnetic resonance data of the compound IV is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.60(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).
example 12
Compound v: synthesis of bis (octadeca-2, 4-dienoyl) phosphatidylcholine
5g of compound IV was transferred to a pressure bottle, excess dry trimethylamine gas was introduced into the system, the pressure bottle was sealed, the reaction was carried out at 60 ℃ for 8 hours, the reaction was carried out by suction filtration, and the filter cake was slurried with acetonitrile to obtain 4.10g of a white waxy solid at a yield of 4.10/(5 × 782.10/802.89) ═ 84.2%.
Wherein, the nuclear magnetic resonance data of the compound IV is as follows, and the structure of the compound is determined according to the attribution of hydrogen atoms:
1H NMR(500MHz,CDCl3)δ7.60(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 parameters in the synthesis process are optimal, and in the esterification reaction, the 2, 4-octadecadienoic acid cannot be lower than 2.0, otherwise, a mono-esterification byproduct is generated, and the yield is reduced; if the amount is excessively added, not only the unreacted 2, 4-octadecadienoic acid is removed, but also the cost is increased; the room temperature in the deprotection reaction can reach the reaction condition, and the reaction time can be shortened by increasing the reaction temperature; the yield of pyridine which is an organic base used in the phosphonylation reaction is higher, and the yield is slightly lower when triethylamine is used as an inorganic base; in the hydrolysis reaction, trimethylamine is excessive, and the gas is used, so that the tightness of the reaction is ensured, and whether the trimethylamine is enough can be judged by using a pH test paper. The synthesis method of the bis (octadeca-2, 4-dienoyl) phosphatidylcholine has the advantages of low cost, high yield and easy industrial production.
The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above examples, and various process schemes having no substantial difference from the concept of the present invention are within the protection scope of the present invention.
Claims (10)
1. A method for preparing bis (octadeca-2, 4-dienoyl) phosphatidylcholine, which is characterized in that: the method comprises the following steps:
(1) carrying out esterification reaction on a compound I, namely 3- (4-methoxy benzyl oxy) -1, 2-propylene glycol and 2, 4-octadecadienoic acid to generate a compound II;
(2) mixing the compound II synthesized in the step (1), namely 2, 4-octadecadienoic acid-3- (4-methoxy benzyl oxy) -1, 2-propylene diester with 2, 3-dichloro-5, 6-dicyan p-benzoquinone, and carrying out ether deprotection reaction to generate a compound III;
(3) carrying out phosphorylation reaction on the compound III synthesized in the step (2), namely 2, 4-octadecadienoic acid-3- (4-methoxy benzyl oxy) -1, 2-glycerol and B-bromoethyl phosphoryl dichloride to generate a compound IV;
(4) and (3) carrying out hydrolysis reaction on the compound IV synthesized in the step (3), namely bis (octadeca-2, 4-dienoyl) bromoethyl phosphate and trimethylamine gas to generate a final product V, namely bis (octadeca-2, 4-dienoyl) phosphatidylcholine.
2. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 1, wherein: the solvent used in the esterification reaction process of the step (1) comprises dichloromethane, and the condensing agent used in the esterification reaction process is dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; the catalyst used in the esterification reaction process is 4-dimethylamino pyridine.
3. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 2, wherein: the molar ratio of the compound I to the condensing agent in the step (1) is 2: 2.5.
4. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 1, wherein: the reaction temperature in the step (1) is 10-20 ℃, and the reaction time is 7-9 h.
5. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 1, wherein: and (2) purifying the compound II generated in the step (1), wherein the purification step comprises suction filtration, acidification, extraction, drying and evaporation to dryness.
6. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 1, wherein: the solvent used in the deprotection reaction in the step (2) is dichloromethane, and the equivalent ratio of the compound II to 2, 3-dichloro-5, 6-dicyan p-benzoquinone is 1.0: 1.0-1.5.
7. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 1, wherein: the reaction temperature in the step (2) is 10 ℃, and the reaction time is 3-5 h.
8. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 1, wherein: and (3) purifying the compound III generated in the step (2), wherein the purification step comprises the steps of washing with a sodium sulfite aqueous solution, extracting, drying and evaporating to obtain a crude product, and the obtained crude product sequentially adopts water, ethanol and PE, EA is 20: 1 beating.
9. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 1, wherein: the solvent used in the phosphorylation reaction in the step (3) is dichloromethane or tetrahydrofuran, and the catalyst used in the phosphorylation reaction is triethylamine or pyridine.
10. The method for producing bis (octadeca-2, 4-dienoyl) phosphatidylcholine according to claim 1, wherein: the reaction temperature of the compound IV and trimethylamine in the step (4) is 30-60 ℃, and the reaction time is 7-10 h.
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| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
|---|
| Facile and Useful Synthesis of Enantiomeric Phosphatidylcholines;Masami Ishihara 等;《Chem. Pharm. Bull.》;19960531;第44卷(第5期);第1096-1098页 * |
| Substrate Chirality and Specificity of Diacylglycerol Kinases and the Multisubstrate Lipid Kinase;Richard M. Epand 等;《Biochemistry》;20071116;第46卷;第14225-14231页 * |
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