CN111087420A - Preparation method of 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid - Google Patents
Preparation method of 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid Download PDFInfo
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- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 22
- -1 (2-cyanoethoxy) (2,2, 2-trichloroethoxy) phosphoryl Chemical group 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- 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 16
- 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 15
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000003536 tetrazoles Chemical class 0.000 claims abstract description 13
- KPWDGTGXUYRARH-UHFFFAOYSA-N 2,2,2-trichloroethanol Chemical compound OCC(Cl)(Cl)Cl KPWDGTGXUYRARH-UHFFFAOYSA-N 0.000 claims abstract description 9
- RKVHNYJPIXOHRW-UHFFFAOYSA-N 3-bis[di(propan-2-yl)amino]phosphanyloxypropanenitrile Chemical compound CC(C)N(C(C)C)P(N(C(C)C)C(C)C)OCCC#N RKVHNYJPIXOHRW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 9
- 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 8
- 230000009471 action Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000005406 washing Methods 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 15
- 238000001704 evaporation Methods 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- 238000004537 pulping Methods 0.000 claims description 9
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000005457 ice water Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 150000003904 phospholipids Chemical class 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 240000001414 Eucalyptus viminalis Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- VPEQMDLSFYEWJR-UHFFFAOYSA-N bis(2-cyanoethyl) [di(propan-2-yl)amino] phosphite Chemical compound N#CCCOP(ON(C(C)C)C(C)C)OCCC#N VPEQMDLSFYEWJR-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000008604 lipoprotein metabolism Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
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 invention discloses a preparation method of 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid, which comprises the following steps: (a) the method comprises the steps of firstly carrying out nucleophilic substitution reaction on dipalmitoyl, namely a compound I and bis (diisopropylamino) (2-cyanoethoxy) phosphine under the action of a solvent and tetrazole, then carrying out reaction on the dipalmitoyl, namely the compound I and trichloroethanol, carrying out mCPBA oxidation to obtain (2R) -3- (((2-cyanoethoxy) (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropyl dipropionate, namely a compound II, (b) carrying out hydrolysis reaction on the compound II and DBU to obtain (2R) -3- (((hydroxy (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropyl dipropionate, namely a compound III, and (c) carrying out hydrolysis reaction on the compound III under the action of acid and zinc powder to obtain the 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid, namely a compound IV Simple and convenient, high total yield, little pollution, low energy consumption, easy separation and purification of products and the like, and is more beneficial to industrialized production.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation method of 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid (DPPA for short).
Background
Phospholipids are a generic name for a class of lipid compounds containing phosphorus, are the main components constituting cell membranes, and have important physiological functions. Research in molecular biology and pharmacology has revealed that phospholipids are involved in many important vital activities in organisms, such as cell signaling, transmission of information in nerve cells, lipoprotein metabolism, and the like. Through the development of many years, the phospholipid has wide application in the fields of food, cosmetics, health care products, pharmaceutical preparations, particularly liposome technology and the like.
There are relevant literature reports on the synthesis of DPPA, mainly including the following two. Route one: using dipalmitin as starting material and POCl3Introducing phospholipid head group, and hydrolyzing to obtain DPPA. The synthetic route is shown below. In this process, POCl is used3Introduction of phospholipid headgroups, POCl3The quality is easy to deteriorate, the storage is not easy, and impurities are easy to bring in; and the reaction is sensitive to water, and the generated impurities are not easy to remove, so that the purity of the final product is poor, and the operation is inconvenient in actual production.
And a second route: using dipalmitin as a starting material, and reacting with bis (2-cyanoethyl) diisopropylamino phosphite ester to introduce a phospholipid head group to obtain an intermediate 3; then DBU is used as alkali, toluene is used as solvent, and the DPPA is obtained after 16h of reflux. The synthetic route is shown below. In this method, step 2 is carried out at a high temperature and for a long time, which is not suitable for industrial production.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a preparation method of 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid. The method has the characteristics of simple and convenient operation, higher total yield, less pollution, low energy consumption, easy separation and purification of products and the like, and is more beneficial to industrial production.
The purpose of the invention is realized as follows:
a method for preparing 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid, comprising the steps of:
a. dipalmitin, namely compound I, firstly undergoes nucleophilic substitution reaction with bis (diisopropylamino) (2-cyanoethoxy) phosphine under the action of a solvent and tetrazole, then reacts with trichloroethanol, and is oxidized by mCPBA to obtain (2R) -3- ((((2-cyanoethoxy) (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropionate dipropyl ester, namely compound II; wherein the content of the first and second substances, the molar weight ratio of the compound I to bis (diisopropylamino) (2-cyanoethoxy) phosphine is 1.0: 1.0-1.2; the molar weight ratio of the compound I to the tetrazole is 1.0: 1.0-1.2; the molar weight ratio of the compound I to the trichloroethanol is 1.0: 1.0; the molar ratio of the compound I to the mCPBA is 1.0: 1.0-2.0; the reaction temperature is 0 ℃; the reaction time is 5 h;
b. the compound II is subjected to hydrolysis reaction under the action of a solvent and alkali to obtain (2R) -3- (((hydroxyl (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropyl dipropionate, namely a compound III, wherein the alkali is DBU, the molar weight ratio of the compound II to the alkali is 1.0: 1.0-1.5, the reaction temperature is 25 ℃, and the reaction time is 2 hours;
c. carrying out hydrolysis reaction on the compound III under the action of a solvent, zinc powder and acid to obtain 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid, namely a compound IV; wherein the acid is acetic acid; the molar weight ratio of the compound III to the zinc powder is 1.0: 2.0-5.0; the reaction temperature is 25 ℃; the reaction time is 3 h; the specific preparation process is shown as the following formula:
wherein, in the step a, the reaction solvent is dichloromethane.
After the reaction in the step a is completed, the method further comprises the following steps: washing with sodium sulfite aqueous solution; washing with sodium carbonate aqueous solution; washing with water; drying; evaporating the solvent to dryness; pulping with methanol for 2 times; carrying out suction filtration; and (5) drying in vacuum.
In step b, the reaction solvent is dichloromethane.
After the reaction in the step b is finished, the method further comprises the following steps: acidifying with 1M hydrochloric acid; washing the organic phase with water; drying with anhydrous sodium sulfate; evaporating the solvent to dryness; column chromatography purification was performed using methanol and dichloromethane at 1: 10.
In the step c, the reaction solvent is tetrahydrofuran, methanol or pyridine; preferably, the reaction solvent is tetrahydrofuran.
After the reaction in the step c is finished, the method further comprises the following steps: dissolving dichloromethane; carrying out suction filtration; evaporating the solvent to dryness; pulping; carrying out suction filtration; and (5) drying.
The invention has the beneficial effect that the target compound is obtained by using the compound I as a starting material. The method has the advantages of short synthetic route, high reaction selectivity, simple post-treatment, high total yield, few byproducts, high purity, stronger route feasibility and easy industrial production.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1
1.1 Synthesis of Compound II, i.e. (2R) -3- ((((2-cyanoethoxy) (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropionic acid dipropyl ester
In a 50mL round bottom flask, 3g of compound I is dissolved in 30mL dichloromethane, an ice water bath is maintained, and 1.59g bis (diisopropylamino) (2-cyanoethoxy) phosphine and 0.37g tetrazole are added; after reacting for 2h at 0 ℃, adding 0.79g of trichloroethanol and 0.37g of tetrazole, and reacting for 2 h; 1.81g mCPBA was added under ice water bath and reacted for 1 h. After the reaction is finished, adding 20mL of saturated sodium sulfite aqueous solution to quench the reaction; washing the organic phase with 20mL of sodium carbonate aqueous solution, washing with water, drying and evaporating to dryness; the crude product was slurried 2 times with 15mL of methanol to give 3.08g of a white solid with a yield of 70%.
1H NMR(500MHz,CDCl3)δ5.27-5.31(m,1H),4.57-4.69(m,2H),4.17-4.38(m,6H),2.77-2.88(m,2H),2.29-2.42(m,4H),1.56-1.71(m,4H),1.21-1.44(m,48H),0.90(t,J＝6.9Hz,6H)。
1.2 Synthesis of Compound II, i.e. (2R) -3- ((((2-cyanoethoxy) (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropionic acid dipropyl ester
In a 50mL round bottom flask, 3g of compound I was dissolved in 30mL of dichloromethane, an ice-water bath was maintained, and 1.9g of bis (diisopropylamino) (2-cyanoethoxy) phosphine and 0.44g of tetrazole were added; after reacting for 2h at 0 ℃, adding 0.79g of trichloroethanol and 0.44g of tetrazole, and reacting for 2 h; 1.81g mCPBA was added under ice water bath and reacted for 1 h. After the reaction is finished, adding 20mL of saturated sodium sulfite aqueous solution to quench the reaction; washing the organic phase with 20mL of sodium carbonate aqueous solution, washing with water, drying and evaporating to dryness; the crude product was slurried 2 times with 15mL of methanol to give 3.52g of a white solid with a yield of 80%.
1H NMR(500MHz,CDCl3)δ5.27-5.31(m,1H),4.57-4.69(m,2H),4.17-4.38(m,6H),2.77-2.88(m,2H),2.29-2.42(m,4H),1.56-1.71(m,4H),1.21-1.44(m,48H),0.90(t,J＝6.9Hz,6H)。
1.3 Synthesis of Compound II, i.e. (2R) -3- ((((2-cyanoethoxy) (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropionic acid dipropyl ester
In a 50mL round bottom flask, 3g of compound I was dissolved in 30mL of dichloromethane, an ice-water bath was maintained, and 1.9g of bis (diisopropylamino) (2-cyanoethoxy) phosphine and 0.44g of tetrazole were added; after reacting for 2h at 0 ℃, adding 0.79g of trichloroethanol and 0.44g of tetrazole, and reacting for 2 h; 0.9g mCPBA was added under ice water bath and reacted for 1 h. After the reaction is finished, adding 20mL of saturated sodium sulfite aqueous solution to quench the reaction; washing the organic phase with 20mL of sodium carbonate aqueous solution, washing with water, drying and evaporating to dryness; the crude product was slurried 2 times with 15mL of methanol to give 2.95g of a white solid in 67% yield.
1H NMR(500MHz,CDCl3)δ5.27-5.31(m,1H),4.57-4.69(m,2H),4.17-4.38(m,6H),2.77-2.88(m,2H),2.29-2.42(m,4H),1.56-1.71(m,4H),1.21-1.44(m,48H),0.90(t,J＝6.9Hz,6H).
1.4 Synthesis of Compound II, i.e. (2R) -3- ((((2-cyanoethoxy) (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropionic acid dipropyl ester
In a 50mL round bottom flask, 3g of compound I was dissolved in 30mL of dichloromethane, an ice-water bath was maintained, and 1.9g of bis (diisopropylamino) (2-cyanoethoxy) phosphine and 0.44g of tetrazole were added; after reacting for 2h at 0 ℃, adding 0.79g of trichloroethanol and 0.44g of tetrazole, and reacting for 2 h; 0.9g mCPBA was added under ice water bath and reacted for 1 h. After the reaction is finished, adding 20mL of saturated sodium sulfite aqueous solution to quench the reaction; washing the organic phase with 20mL of sodium carbonate aqueous solution, washing with water, drying and evaporating to dryness; the crude product was slurried 2 times with 15mL of methanol to give 3.26g of a white solid in 74% yield.
1H NMR(500MHz,CDCl3)δ5.27-5.31(m,1H),4.57-4.69(m,2H),4.17-4.38(m,6H),2.77-2.88(m,2H),2.29-2.42(m,4H),1.56-1.71(m,4H),1.21-1.44(m,48H),0.90(t,J＝6.9Hz,6H)。
Example 2
2.1 Synthesis of Compound III, namely (2R) -3- (((hydroxy (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropyl dipropionate
In a 25mL round-bottom flask, 3g of Compound II was dissolved in 15mL of methylene chloride, and 0.55g of DBU was added to react at room temperature for 2 hours. Acidifying with 20mL of 1M dilute hydrochloric acid, extracting with 15mL of dichloromethane, washing the organic phase with 20mL of 1M dilute hydrochloric acid once, washing with 20mL of water once, drying with anhydrous sodium sulfate, and evaporating to dryness. The crude product was purified by column chromatography using methanol and dichloromethane 1:10 to give 2.21g of a white gum in 79% yield.
1H NMR(500MHz,CDCl3)δ5.27-5.31(m,1H),4.91(d,J＝17.0Hz,2H),4.33-4.47(m,2H),4.10-4.18(m,2H),2.29-2.42(m,4H),1.56-1.71(m,4H),1.21-1.44(m,48H),0.90(t,J＝6.9Hz,6H)。
2.2 Synthesis of Compound III, namely (2R) -3- (((hydroxy (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropyl dipropionate
In a 25mL round-bottom flask, 3g of Compound II was dissolved in 15mL of methylene chloride, and 0.66g of DBU was added and reacted at room temperature for 2 hours. Acidifying with 20mL of 1M dilute hydrochloric acid, extracting with 15mL of dichloromethane, washing the organic phase with 20mL of 1M dilute hydrochloric acid once, washing with 20mL of water once, drying with anhydrous sodium sulfate, and evaporating to dryness. The crude product was purified by column chromatography using methanol and dichloromethane 1:10 to give 2.53g of a white gum in 90% yield.
1H NMR(500MHz,CDCl3)δ5.27-5.31(m,1H),4.91(d,J＝17.0Hz,2H),4.33-4.47(m,2H),4.10-4.18(m,2H),2.29-2.42(m,4H),1.56-1.71(m,4H),1.21-1.44(m,48H),0.90(t,J＝6.9Hz,6H)。
2.3 Synthesis of Compound III, namely (2R) -3- (((hydroxy (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropyl dipropionate
In a 25mL round-bottom flask, 3g of Compound II was dissolved in 15mL of methylene chloride, and 0.82g of DBU was added and reacted at room temperature for 2 hours. Acidifying with 20mL of 1M dilute hydrochloric acid, extracting with 15mL of dichloromethane, washing the organic phase with 20mL of 1M dilute hydrochloric acid once, washing with 20mL of water once, drying with anhydrous sodium sulfate, and evaporating to dryness. The crude product was purified by column chromatography using methanol and dichloromethane 1:10 to give 2.32g of a white gum in 83% yield.
1H NMR(500MHz,CDCl3)δ5.27-5.31(m,1H),4.91(d,J＝17.0Hz,2H),4.33-4.47(m,2H),4.10-4.18(m,2H),2.29-2.42(m,4H),1.56-1.71(m,4H),1.21-1.44(m,48H),0.90(t,J＝6.9Hz,6H)。
Example 3
3.1 Synthesis of Compound IV, 1, 2-dipalmitoyl-SN-Glycerol-3-phosphoric acid
In a 25mL round bottom flask, 3g of Compound III was dissolved in 15mL of methanol, and 5mL of acetic acid and 1.25g of zinc powder were added to react at room temperature for 3 hours. TLC monitors the reaction to be complete, 20mL dichloromethane is added, the mixture is stirred for 5min and then is filtered to remove zinc powder, the solvent is evaporated, 15mL acetonitrile is added for pulping for 2 times, and the mixture is filtered, dried to obtain 1.85g of white solid with the yield of 74 percent.
1H NMR(500MHz,CDCl3) δ 5.15(s,1H),4.30-4.36(m,1H),4.10-4.14(m,1H),3.85-3.93(m,2H),2.21-2.25(m,4H),1.52(s,4H),1.12-1.33(m,48H),0.79(t, J ═ 6.4Hz, 6H). 3.2 Synthesis of Compound IV, 1, 2-dipalmitoyl-SN-Glycerol-3-phosphoric acid
In a 25mL round bottom flask, 3g of Compound III was dissolved in 15mL of tetrahydrofuran, and 5mL of acetic acid and 1.25g of zinc powder were added to react at room temperature for 3 hours. TLC monitors the reaction to be complete, 20mL of dichloromethane is added, the mixture is stirred for 5min and then is filtered to remove zinc powder, the solvent is evaporated to dryness, 15mL of acetonitrile is added for pulping for 2 times, and the mixture is filtered, dried to obtain 2.15g of white solid with the yield of 86%.
1H NMR(500MHz,CDCl3) δ 5.15(s,1H),4.30-4.36(m,1H),4.10-4.14(m,1H),3.85-3.93(m,2H),2.21-2.25(m,4H),1.52(s,4H),1.12-1.33(m,48H),0.79(t, J ═ 6.4Hz, 6H). 3.3 Synthesis of Compound IV, 1, 2-dipalmitoyl-SN-Glycerol-3-phosphoric acid
In a 25mL round bottom flask, 3g of Compound III was dissolved in 15mL of pyridine, and 5mL of acetic acid and 1.25g of zinc powder were added to react at room temperature for 3 hours. TLC monitors the reaction to be complete, 20mL dichloromethane is added, the mixture is stirred for 5min and then is filtered to remove zinc powder, the solvent is evaporated, 15mL acetonitrile is added for pulping for 2 times, and the mixture is filtered, dried to obtain 1.33g of white solid with the yield of 53 percent.
1H NMR(500MHz,CDCl3) δ 5.15(s,1H),4.30-4.36(m,1H),4.10-4.14(m,1H),3.85-3.93(m,2H),2.21-2.25(m,4H),1.52(s,4H),1.12-1.33(m,48H),0.79(t, J ═ 6.4Hz, 6H). 3.4 Synthesis of Compound IV, 1, 2-dipalmitoyl-SN-Glycerol-3-phosphoric acid
In a 25mL round bottom flask, 3g of Compound III was dissolved in 15mL of tetrahydrofuran, and 5mL of acetic acid and 0.5g of zinc powder were added to react at room temperature for 3 hours. TLC monitors the reaction to be complete, 20mL dichloromethane is added, the mixture is stirred for 5min and then is filtered to remove zinc powder, the solvent is evaporated, 15mL acetonitrile is added for pulping for 2 times, and the mixture is filtered, dried to obtain 1.58g of white solid with the yield of 63%.
1H NMR(500MHz,CDCl3) δ 5.15(s,1H),4.30-4.36(m,1H),4.10-4.14(m,1H),3.85-3.93(m,2H),2.21-2.25(m,4H),1.52(s,4H),1.12-1.33(m,48H),0.79(t, J ═ 6.4Hz, 6H). 3.5 Synthesis of Compound IV, 1, 2-dipalmitoyl-SN-Glycerol-3-phosphoric acid
In a 25mL round bottom flask, 3g of Compound III was dissolved in 15mL of tetrahydrofuran, and 5mL of acetic acid and 0.75g of zinc powder were added to react at room temperature for 3 hours. TLC monitors the reaction to be complete, 20mL dichloromethane is added, the mixture is stirred for 5min and then is filtered to remove zinc powder, the solvent is evaporated, 15mL acetonitrile is added for pulping for 2 times, and the mixture is filtered, dried to obtain 1.75g of white solid with the yield of 70%.
1H NMR(500MHz,CDCl3)δ5.15(s,1H),4.30-4.36(m,1H),4.10-4.14(m,1H),3.85-3.93(m,2H),2.21-2.25(m,4H),1.52(s,4H),1.12-1.33(m,48H),0.79(t,J＝6.4Hz,6H)。
In conclusion, the method for preparing the 1, 2-dipalmitoyl-SN-glycerol-3-phosphorylethanolamine has the advantages of short synthetic route, simple and convenient operation, low cost and high yield.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (4)
1. A preparation method of 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid is characterized by comprising the following specific steps:
step 1: dipalmitin, namely compound I, firstly carries out nucleophilic substitution reaction with bis (diisopropylamino) (2-cyanoethoxy) phosphine under the action of a solvent and tetrazole, then reacts with trichloroethanol, and is oxidized by mCPBA to obtain (2R) -3- ((((2-cyanoethoxy) (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropionate, namely compound II; wherein the content of the first and second substances, the molar weight ratio of the compound I to bis (diisopropylamino) (2-cyanoethoxy) phosphine is 1.0: 1.0-1.2; the molar weight ratio of the compound I to the tetrazole is 1.0: 1.0-1.2; the molar weight ratio of the compound I to the trichloroethanol is 1.0: 1.0; the molar ratio of the compound I to the mCPBA is 1.0: 1.0-2.0; the reaction temperature is 0 ℃; the reaction time is 5 h;
step 2: the compound II is subjected to hydrolysis reaction under the action of a solvent and alkali to obtain (2R) -3- (((hydroxyl (2,2, 2-trichloroethoxy) phosphoryl) oxy) propane-1, 2-dipropyl dipropionate, namely a compound III, wherein the alkali is DBU, the molar ratio of the compound II to the alkali is 1.0: 1.0-1.5, the reaction temperature is 25 ℃, and the reaction time is 2 hours;
and step 3: carrying out hydrolysis reaction on the compound III under the action of a solvent, zinc powder and acid to obtain 1, 2-dipalmitoyl-SN-glycerol-3-phosphoric acid, namely a compound IV; wherein the acid is acetic acid; the molar weight ratio of the compound III to the zinc powder is 1.0: 2.0-5.0; the reaction temperature is 25 ℃; the reaction time is 3 h; the specific preparation process is shown as the following formula:
2. the method according to claim 1, wherein in step 1, the solvent is dichloromethane; after the reaction is finished, the method further comprises the following steps: washing with sodium sulfite aqueous solution; washing with sodium carbonate aqueous solution; washing with water; drying; evaporating the solvent to dryness; pulping; carrying out suction filtration; and (5) drying in vacuum.
3. The method according to claim 1, wherein in step 2, the solvent is dichloromethane; after the reaction is finished, the method further comprises the following steps: acidifying with 1M hydrochloric acid; washing the organic phase with water; drying with anhydrous sodium sulfate; evaporating the solvent to dryness; and (5) purifying by column chromatography.
4. The method according to claim 1, wherein in step 3, the solvent is tetrahydrofuran or methanol; after the reaction is finished, the method further comprises the following steps: dissolving dichloromethane; carrying out suction filtration; evaporating the solvent to dryness; pulping; carrying out suction filtration; and (5) drying.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002018946A2 (en) * | 2000-08-23 | 2002-03-07 | The Babraham Institute | Immobilised phosphatidic acid probe |
| CN110330524A (en) * | 2019-07-10 | 2019-10-15 | 安徽昊帆生物有限公司 | Bis- palmityl-SN- glycerol -3- phosphatidyl ethanolamine of 1,2- and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002018946A2 (en) * | 2000-08-23 | 2002-03-07 | The Babraham Institute | Immobilised phosphatidic acid probe |
| CN110330524A (en) * | 2019-07-10 | 2019-10-15 | 安徽昊帆生物有限公司 | Bis- palmityl-SN- glycerol -3- phosphatidyl ethanolamine of 1,2- and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| ROSSETO, RENATO ET AL.: "A new approach to phospholipid synthesis using tetrahydropyranyl glycerol: rapid access to phosphatidic acid and phosphatidylcholine, including mixed-chain glycerophospholipid derivatives", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
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