CN117143145A - Preparation method of dioleoyl phosphatidylethanolamine - Google Patents
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- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 83
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims abstract description 39
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 17
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims abstract description 15
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims abstract description 15
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000005642 Oleic acid Substances 0.000 claims abstract description 15
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000005886 esterification reaction Methods 0.000 claims abstract description 15
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 14
- IYRULVWLVRRRIS-UHFFFAOYSA-N tert-butyl 3-amino-2-hydroxypropanoate Chemical compound CC(C)(C)OC(=O)C(O)CN IYRULVWLVRRRIS-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims abstract description 13
- 235000009518 sodium iodide Nutrition 0.000 claims abstract description 13
- 238000006467 substitution reaction Methods 0.000 claims abstract description 13
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 12
- SNVCRNWSNUUGEA-UHFFFAOYSA-N dichlorophosphoryloxymethane Chemical compound COP(Cl)(Cl)=O SNVCRNWSNUUGEA-UHFFFAOYSA-N 0.000 claims abstract description 9
- RNVYQYLELCKWAN-RXMQYKEDSA-N [(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)OC[C@@H](CO)O1 RNVYQYLELCKWAN-RXMQYKEDSA-N 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 230000035484 reaction time Effects 0.000 claims description 16
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical group CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 claims description 14
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 230000005012 migration Effects 0.000 abstract description 2
- 238000013508 migration Methods 0.000 abstract description 2
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 abstract 1
- 238000004809 thin layer chromatography Methods 0.000 description 36
- -1 cationic phospholipid Chemical class 0.000 description 29
- 238000001704 evaporation Methods 0.000 description 23
- 238000001914 filtration Methods 0.000 description 19
- 238000001035 drying Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- UMHYVXGZRGOICM-AUYXYSRISA-N 2-[(z)-octadec-9-enoyl]oxypropyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC\C=C/CCCCCCCC UMHYVXGZRGOICM-AUYXYSRISA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000004537 pulping Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 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 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 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 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229940074076 glycerol formal Drugs 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000000865 phosphorylative effect Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940045860 white wax Drugs 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000008777 Glycerylphosphorylcholine Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 102000011420 Phospholipase D Human genes 0.000 description 2
- 108090000553 Phospholipase D Proteins 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 description 2
- 229960004956 glycerylphosphorylcholine Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000005538 phosphinite group Chemical group 0.000 description 2
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- VBFFCPDBXIGRLO-UHFFFAOYSA-N dichloro methyl phosphate Chemical compound COP(=O)(OCl)OCl VBFFCPDBXIGRLO-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- DOWWCCDWPKGNGX-UHFFFAOYSA-N methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate Chemical compound COC(=O)C1COC(C)(C)O1 DOWWCCDWPKGNGX-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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 provides a preparation method of dioleoyl phosphatidylethanolamine, which comprises the following steps: s1, enabling (R) -glycerol acetonide, methyl dichlorophosphate and Boc-ethanolamine to undergo nucleophilic substitution reaction to obtain an intermediate I; s2, carrying out hydrolysis reaction on the intermediate I to obtain an intermediate II; s3, enabling the intermediate II and oleic acid to perform esterification reaction to obtain an intermediate III; s4, enabling the intermediate III and sodium iodide to undergo substitution reaction to obtain an intermediate IV; s5, the intermediate IV is subjected to Boc removal protection reaction to generate the dioleoyl phosphatidylethanolamine. According to the preparation method provided by the embodiment of the invention, the target product dioleoyl phosphatidylethanolamine is finally obtained by adopting the simple (R) -glyceroglycol acetonide as a starting raw material through nucleophilic substitution, hydrolysis, esterification reaction and the like, the chirality of the compound in the reaction is not changed, the migration of groups is less, the synthetic route is short, and the yield is higher.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of dioleoyl phosphatidylethanolamine.
Background
PE-type phosphinites are an important component of LDL phosphinites and are a major component of some brain and retinal membranes. Can also be used for liver parasitic diseases, novel targeted liposome, can reduce toxic and side effects, and can be applied clinically as a drug carrier.
The dioleoyl phosphatidylethanolamine, also called 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (also called DOPE for short), is a common auxiliary phospholipid, can stabilize a double-layer membrane, reduce toxicity of positive components, can assist cell permeation of cationic liposome, and improves transmembrane efficiency. Therefore, the addition of DOPE can lead the cationic liposome membrane to be fused better, have higher stability and smaller cytotoxicity. In addition, DOPE is neutral auxiliary lipid of cationic liposome, and is combined with cationic phospholipid to improve transfection efficiency of naked siRNA.
There have been reports on the synthesis of 1, 2-dioleoyl-sn-glycero-3-phosphorylethanolamine. The literature reports that there are two synthetic routes for 1, 2-dioleoyl-sn-glycero-3-phosphorylethanolamine.
Route one: as shown in the reaction formula (1):
in the synthetic route, oleic acid is activated by DCC and then reacts with GPC (glycerophosphorylcholine) and DBU to obtain an intermediate PC (dioleoyl phosphatidylcholine); PC reacts with ethanolamine under the action of phospholipase D to obtain the target compound. However, phospholipase D used in this scheme is expensive and the synthesis cost is high.
Route two: as shown in the reaction formula (2):
in the synthetic route, oleic acid diacylglycerol is taken as a raw material, and reacts with a phosphine reagent to obtain an intermediate, and the intermediate reacts with ammonia to obtain a target product. However, the oleic acid diacylglycerol in the scheme is prepared from 2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid methyl ester through 6 steps of reaction, the reaction steps are complicated, the atom economy is poor, and the total yield is low.
Disclosure of Invention
In view of the above, the present invention aims to provide a process for producing dioleoyl phosphatidylethanolamine with high yield and low cost.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of the dioleoyl phosphatidylethanolamine comprises the following steps:
s1, enabling (R) -glycerol acetonide, methyl dichlorophosphate and Boc-ethanolamine to undergo nucleophilic substitution reaction to obtain an intermediate I;
s2, carrying out hydrolysis reaction on the intermediate I to obtain an intermediate II;
s3, enabling the intermediate II and oleic acid to perform esterification reaction to obtain an intermediate III;
s4, enabling the intermediate III and sodium iodide to undergo substitution reaction to obtain an intermediate IV;
s5, the intermediate IV is subjected to Boc removal protection reaction to generate the dioleoyl phosphatidylethanolamine.
Further, the nucleophilic substitution reaction in the step S1 is performed in a first solvent under the action of a first condensing agent, wherein the first solvent is toluene, dichloromethane, or a mixture thereof, and the first condensing agent is tetramethylpiperidine.
Further, the (R) -acetonide glycerol: methyl dichlorophosphate: boc-ethanolamine: the molar ratio of the tetramethylpiperidine is 1: (1.0-1.5): (1.0-1.5): (1.5-2.0).
Further, the reaction temperature of the nucleophilic substitution reaction is 0-30 ℃ and the reaction time is 5-20 hours.
Further, the hydrolysis reaction of step S2 is performed in a second solvent in the presence of a first acid, the first acid being toluene sulfonic acid, trifluoroacetic acid, or a mixture thereof, and the second solvent being methanol.
Further, the reaction temperature of the hydrolysis reaction is-30-20 ℃ and the reaction time is 5-10 hours.
Further, the esterification reaction in the step S3 is performed under the action of a second condensing agent and a catalyst, wherein the second condensing agent is dicyclohexylcarbodiimide, and the catalyst is 4-dimethylaminopyridine.
Further, the intermediate II: oleic acid: a second condensing agent: the molar ratio of the catalyst is 1: (1.8-2.2): (2.0-2.4): (0.01-0.1).
Further, the substitution reaction of step S4 is performed in acetonitrile solvent, the intermediate III: the molar ratio of sodium iodide is 1 (1.0-1.5), the reaction temperature of the substitution reaction is 35-80 ℃, and the reaction time is 2-10 hours.
Further, the Boc removal protection reaction in the step S5 is performed in a dichloromethane solvent in the presence of a second acid, wherein the second acid is trifluoroacetic acid, the reaction temperature of the deprotection reaction is 0-30 ℃, and the reaction time is 16-20 hours.
The technical scheme of the invention has at least one of the following beneficial effects:
according to the preparation method provided by the embodiment of the invention, the simple (R) -glycerol formal is adopted as the initial raw material, and the target product, namely the dioleoyl phosphatidylethanolamine (namely (R) -dioleoyl-sn-glycero-3-phosphorylethanolamine, DOPE) is finally obtained through nucleophilic substitution, hydrolysis, esterification reaction and the like, wherein the chiral group of the compound does not participate in subsequent reaction in the reaction, so that the chirality of the compound is not changed, the migration of the group is less, the synthetic route is short, the yield is higher, and the total yield can reach more than 60%;
the preparation method does not use expensive reagents, and reduces the production cost;
the preparation method provided by the invention is simple and convenient to operate, mild and controllable in conditions, and can be used for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
The following first describes in detail the preparation method of dioleoyl phosphatidylethanolamine, DOPE, according to an embodiment of the present invention.
According to the preparation method of the dioleoyl phosphatidylethanolamine, the synthetic route is shown as the following formula (3):
specifically, the preparation method of the dioleoyl phosphatidylethanolamine comprises the following steps:
s1, nucleophilic substitution reaction is carried out on (R) -glycerol formal, dichloro methyl phosphate and Boc-ethanolamine to obtain an intermediate I.
Specifically, referring to the above synthetic route, this step is the first step in the above formula (3), in which (R) -glycerylacetone is used as a starting material, and nucleophilic substitution reaction is performed with methyl dichlorophosphate and Boc-ethanolamine to obtain intermediate I shown in the above formula (3).
That is, according to the preparation method of the present invention, simple (R) -glycerylacetone is used as a starting material, and the cost of the starting material is low.
Further, the nucleophilic substitution reaction in the step S1 is performed in a first solvent under the action of a first condensing agent, wherein the first solvent is toluene, dichloromethane, or a mixture thereof, and the first condensing agent is tetramethylpiperidine. In the solvent, the starting raw materials (R) -glycerol formal and methyl dichlorophosphate, boc-ethanolamine and even tetramethyl piperidine serving as a condensing agent for the reaction in the step can be well dissolved, so that the reaction is facilitated.
In some embodiments, the (R) -acetonide is: methyl dichlorophosphate: boc-ethanolamine: the molar ratio of the tetramethylpiperidine is 1: (1.0-1.5): (1.0-1.5): (1.5-2.0).
That is, the use of an excess of methyl dichlorophosphate, boc-ethanolamine, and tetramethylpiperidine relative to stoichiometry helps to increase the use of (R) -acetonide.
Further, the reaction temperature of the nucleophilic substitution reaction is 0-30 ℃ and the reaction time is 5-20 hours. The reaction condition is mild, and the method is suitable for industrial mass production.
In some embodiments of the present invention, after the nucleophilic substitution reaction of step S1 is completed, it may further include: filtering, drying, evaporating, and purifying by column. Thus, impurities such as reactants not involved in the reaction can be removed, and unnecessary byproducts can be prevented from being introduced in the subsequent steps.
S2, carrying out hydrolysis reaction on the intermediate I to obtain an intermediate II.
That is, as shown in the above synthetic route, after intermediate I is obtained, it is hydrolyzed so that the terminal is converted into a hydroxyl group.
In some embodiments of the invention, the hydrolysis reaction of step S2 is performed in a second solvent in the presence of a first acid, the first acid being toluene sulfonic acid, trifluoroacetic acid, or a mixture thereof, and the second solvent being methanol. That is, intermediate I undergoes the hydrolysis reaction described above under the conditions of the organic acid described above. In addition, the organic acid can be well dissolved in methanol, which is beneficial to the hydrolysis reaction.
Further, the reaction temperature of the hydrolysis reaction is-30-20 ℃ and the reaction time is 5-10 hours.
Further, in some embodiments of the present invention, after the hydrolysis reaction of step S2 is completed, the method may further include: triethylamine was used to adjust the pH to neutral, after which the solvent was dried and evaporated to dryness to give intermediate II.
S3, enabling the intermediate II to carry out esterification reaction with oleic acid to obtain an intermediate III.
That is, as shown in the above synthetic route, after intermediate II is obtained, it is further subjected to esterification reaction with oleic acid to obtain intermediate III shown in III.
Further, the esterification reaction in the step S3 is performed under the action of a second condensing agent and a catalyst, wherein the second condensing agent is dicyclohexylcarbodiimide, and the catalyst is 4-dimethylaminopyridine. By using a condensing agent and a catalyst, the reaction rate and the yield are advantageously improved.
Further, the intermediate II: oleic acid: a second condensing agent: the molar ratio of the catalyst is 1: (1.8-2.2): (2.0-2.4): (0.01-0.1). Preferably 1: (1.8-2.2): (2.0-2.4): 0.05.
the esterification reaction in step S3 may be performed in, for example, methylene chloride, toluene, or a mixture thereof.
In some embodiments of the present invention, the reaction temperature of the esterification reaction in step S3 is 0 to 30 ℃ and the reaction time is 5 to 30 hours.
In some embodiments of the present invention, the esterification reaction of step S3 may further include: filtering, evaporating to dryness, and purifying by column.
S4, carrying out substitution reaction on the intermediate III and sodium iodide to obtain an intermediate IV.
That is, after the esterification reaction to obtain intermediate III, further, it is subjected to substitution reaction with sodium iodide to obtain intermediate IV represented by IV in the above formula (3).
Further, the substitution reaction of step S4 is performed in acetonitrile or acetone solvent, the intermediate III: the molar ratio of sodium iodide is 1 (1.0-1.5), the reaction temperature of the substitution reaction is 35-80 ℃, and the reaction time is 2-10 hours. The sodium iodide is used in proper excess, and under the heating condition, the reaction is promoted, and the yield is improved.
In some embodiments of the present invention, the substitution reaction of step S4 may further include: filtering, evaporating to dryness, recrystallizing, purifying, acidifying, drying and evaporating to dryness.
S5, the intermediate IV is subjected to Boc removal protection reaction to generate the dioleoyl phosphatidylethanolamine.
That is, after the intermediate IV is obtained through the above multi-step reaction, finally, the Boc protecting group is removed, and the target product DOPE is obtained.
Further, the Boc removal protection reaction in the step S5 is performed in a dichloromethane solvent in the presence of a second acid, wherein the second acid is trifluoroacetic acid, the reaction temperature of the deprotection reaction is 0-30 ℃, and the reaction time is 16-20 hours. That is, the removal of the Boc protecting group is performed in the presence of trifluoroacetic acid.
In some embodiments of the present invention, the Boc deprotection reaction of step S5 may further comprise, after completion: drying, evaporating the solvent, adding methanol and sodium acetate for dissociation, filtering, pulping and purifying to obtain DOPE product. After DOPE is obtained, further purification treatment may be performed as needed.
The preparation method of the present invention is described in further detail below in connection with specific examples.
(one) intermediate I: synthesis of tert-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate
Example 1
1g of (R) -glycerylacetone and 1.13g of dichlorophosphoryl methyl ester were dissolved in 10mL of Dichloromethane (DCM), and 1.60g of tetramethylpiperidine was added under ice water. The reaction temperature was 10deg.C, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 5 hours. 1.22g Boc-ethanolamine and 1.60g tetramethylpiperidine were added, the reaction temperature was 10℃and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) and reacted for 5 hours. Cooling in ice water bath, filtering, drying with anhydrous sodium sulfate, and evaporating. Purification by column gave compound I1.79 g in 64% yield.
Example 2
1g of (R) -glycerylacetone and 1.46g of dichlorophosphoryl methyl ester were dissolved in 10mL of Dichloromethane (DCM), and 1.92g of tetramethylpiperidine was added under ice water. The reaction temperature was 10deg.C, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 5 hours. 1.59g Boc-ethanolamine and 1.92g tetramethylpiperidine were added, the reaction temperature was 10℃and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) and reacted for 5 hours. Cooling in ice water bath, filtering, drying with anhydrous sodium sulfate, and evaporating. Purification by column gave 2.18g of Compound I in 78% yield.
Example 3
1g of (R) -glycerylacetone and 1.69g of dichlorophosphoryl methyl ester were dissolved in 10mL of Dichloromethane (DCM) and 2.13g of tetramethylpiperidine were added under ice water. The reaction temperature was 10deg.C, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 5 hours. 1.83g Boc-ethanolamine and 2.13g tetramethylpiperidine were added, the reaction temperature was 10℃and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) and reacted for 5 hours. Cooling in ice water bath, filtering, drying with anhydrous sodium sulfate, and evaporating. Purification by column gave 2.37g of Compound I in 85% yield.
(II) intermediate II: synthesis of tert-butyl (2- ((((R) -2, 3-dihydroxypropoxy) (methoxy) phosphoryl) oxy) ethyl) carbamate
Example 4
2g of tert-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate are dissolved in 20mL of methanol and 2g of trifluoroacetic acid are added. The reaction temperature was 0deg.C, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 5 hours. Triethylamine is added to adjust to neutral, filtering is carried out, and 1.46g of compound II is obtained after evaporation to dryness, and the yield is 82%.
Example 5
2g of tert-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate are dissolved in 20mL of methanol and 2g of concentrated hydrochloric acid are added. The reaction temperature was 0deg.C, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 5 hours. Triethylamine is added to adjust to neutral, filtering is carried out, and 1.58g of compound II is obtained after evaporation, and the yield is 89%.
Example 6
2g of tert-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate are dissolved in 20mL of methanol and 2g of p-toluenesulfonic acid are added. The reaction temperature was 0deg.C, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 5 hours. Triethylamine is added to adjust to neutral, filtering is carried out, and 1.62g of compound II is obtained after evaporation to dryness, and the yield is 91%.
(III) intermediate III: synthesis of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (methoxy) phosphorylating) oxy) propane-1, 2-diyldioleate
Example 7
2g of tert-butyl (2- ((((R) -2, 3-dihydroxypropoxy) (methoxy) phosphoryl) oxy) ethyl) carbamate was added to 20mL of Dichloromethane (DCM), 3.09g of oleic acid and 0.04g of 4-dimethylaminopyridine were added, and 2.51g of dicyclohexylcarbodiimide was further added to the reaction solution. The reaction temperature was 10deg.C, and the reaction time was monitored by Thin Layer Chromatography (TLC). Filtering, drying by anhydrous sodium sulfate, and evaporating to obtain 4.06g of compound III with a yield of 78%.
Example 8
2g of tert-butyl (2- ((((R) -2, 3-dihydroxypropoxy) (methoxy) phosphoryl) oxy) ethyl) carbamate was added to 20mL of Dichloromethane (DCM), 3.43g of oleic acid and 0.04g of 4-dimethylaminopyridine were added, and 2.75g of dicyclohexylcarbodiimide was added to the reaction solution. The reaction temperature was 10deg.C, and the reaction time was monitored by Thin Layer Chromatography (TLC). Filtering, drying by anhydrous sodium sulfate, and evaporating to obtain 4.48g of compound III with 86% yield.
Example 9
2g of tert-butyl (2- ((((R) -2, 3-dihydroxypropoxy) (methoxy) phosphoryl) oxy) ethyl) carbamate was added to 20mL of Dichloromethane (DCM), 3.77g of oleic acid and 0.04g of 4-dimethylaminopyridine were added, and 3.01g of dicyclohexylcarbodiimide was further added to the reaction solution. The reaction temperature was 10deg.C, and the reaction time was monitored by Thin Layer Chromatography (TLC). Filtering, drying by anhydrous sodium sulfate, and evaporating to obtain 4.74g of compound III with a yield of 91%.
(IV) intermediate IV: synthesis of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (hydroxy) phosphorylating) oxy) propane-1, 2-diyldioleate
Example 10
2g of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (methoxy) phosphoryl) oxy) propane-1, 2-diyldioleate was dissolved in 20mL of acetonitrile, and 0.35g of sodium iodide was added. The reaction temperature was 60℃and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 4h. Filtering, evaporating to dryness, recrystallizing, purifying, acidifying, drying with anhydrous sodium sulfate, evaporating to dryness to obtain compound IV 1.59g, and the yield is 81%.
Example 11
2g of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (methoxy) phosphoryl) oxy) propane-1, 2-diyldioleate were dissolved in 20mL of acetone, and 0.70g of sodium iodide was added. The reaction temperature was 30deg.C, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 20 hours. Filtering, evaporating to dryness, recrystallizing, purifying, acidifying, drying with anhydrous sodium sulfate, evaporating to dryness to obtain compound IV 1.41g with a yield of 72%.
Example 12
Compound IV: synthesis of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (hydroxy) phosphorylating) oxy) propane-1, 2-diyldioleate
2g of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (methoxy) phosphoryl) oxy) propane-1, 2-diyldioleate were dissolved in 20mL of acetone, and 0.70g of sodium iodide was added. The reaction temperature was 60℃and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 4h. Filtering, evaporating to dryness, recrystallizing, purifying, acidifying, drying with anhydrous sodium sulfate, evaporating to dryness to obtain compound IV 1.87g, and the yield is 95%.
(V) target product: synthesis of (R) -dioleoyl-sn-glycero-3-phosphato ethanolamine
Example 13
2g of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (hydroxy) phosphorylated) oxy) propane-1, 2-diyldioleate was dissolved in 20mL of methylene chloride, 2g of acetic acid and 1mL of water were added, the reaction temperature was 30 ℃, the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 20 hours. Drying, evaporating to dryness, pulping into 20mL of methanol and 2g of sodium acetate, stirring for 1h to obtain sodium salt, filtering, pulping and purifying. 1.37g of white wax was obtained in 78% yield.
Example 14
2g of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (hydroxy) phosphorylated) oxy) propane-1, 2-diyldioleate was dissolved in 4mL of methylene chloride, 2g of trifluoroacetic acid was added, the reaction temperature was 30 ℃, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and the reaction was continued for 12 hours. Drying, evaporating to dryness, pulping into 20mL of methanol and 2g of sodium acetate, stirring for 1h to obtain sodium salt, filtering, pulping and purifying. 1.45g of white wax was obtained in 82% yield.
Example 15
2g of (2R) -3- ((2- ((tert-butylcarbonyl) amino) ethoxy) (hydroxy) phosphorylated) oxy) propane-1, 2-diyldioleate was dissolved in 6mL of methylene chloride, 2g of p-toluenesulfonic acid was added, the reaction temperature was 30 ℃, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) and reacted for 8 hours. Drying, evaporating to dryness, pulping into 20mL of methanol and 2g of sodium acetate, stirring for 1h to obtain sodium salt, filtering, pulping and purifying. 1.57g of white wax was obtained in 89% yield.
From the analysis, the substitution reaction uses excessive dichlorophosphoryl methyl ester and Boc-ethanolamine to make the yield higher; in the hydrolysis reaction, the p-toluenesulfonic acid enables the hydrolysis to be more sufficient; more oleic acid and excessive condensing agent DCC in the esterification reaction can make the reaction more sufficient; in the demethylation process, excessive sodium iodide is added to enable the reaction to be more sufficient, and heating can enable the reaction to be faster; the trifluoroacetic acid system is more sufficient in the reaction of removing the protecting group.
In conclusion, the synthetic method of the (R) -dioleoyl-sn-glycero-3-phosphorylethanolamine has the advantages of short synthetic route, mild condition, high efficiency and easy industrial production.
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The preparation method of the dioleoyl phosphatidylethanolamine is characterized by comprising the following steps of:
step S1, nucleophilic substitution reaction is carried out on (R) -glycerol acetonide, methyl dichlorophosphate and Boc-ethanolamine to obtain an intermediate I;
step S2, carrying out hydrolysis reaction on the intermediate I to obtain an intermediate II;
step S3, enabling the intermediate II and oleic acid to undergo esterification reaction to obtain an intermediate III;
step S4, carrying out substitution reaction on the intermediate III and sodium iodide to obtain an intermediate IV;
and S5, performing Boc removal protection reaction on the intermediate IV to generate the dioleoyl phosphatidylethanolamine.
2. The method according to claim 1, wherein the nucleophilic substitution reaction in step S1 is performed in a first solvent under the action of a first condensing agent, wherein the first solvent is toluene, methylene chloride, or a mixture thereof, and the first condensing agent is tetramethylpiperidine.
3. The method according to claim 2, wherein the (R) -acetonide is glycerol: methyl dichlorophosphate: boc-ethanolamine: the molar ratio of the tetramethylpiperidine is 1: (1.0-1.5): (1.0-1.5): (1.5-2.0).
4. The method according to claim 2, wherein the nucleophilic substitution reaction is carried out at a reaction temperature of 0 to 30 ℃ for a reaction time of 5 to 20 hours.
5. The process of claim 1, wherein the hydrolysis reaction is carried out in a second solvent in the presence of a first acid, the first acid being toluene sulfonic acid, trifluoroacetic acid, or a mixture thereof, and the second solvent being methanol.
6. The method according to claim 5, wherein the hydrolysis reaction is carried out at a reaction temperature of-30 to 20 ℃ for a reaction time of 5 to 10 hours.
7. The process of claim 1 wherein the esterification reaction is carried out with a second condensing agent that is dicyclohexylcarbodiimide and a catalyst that is 4-dimethylaminopyridine.
8. The method of claim 7, wherein the intermediate II: oleic acid: a second condensing agent: the molar ratio of the catalyst is 1: (1.8-2.2): (2.0-2.4): (0.01-0.1).
9. The process according to claim 1, wherein the substitution reaction in step S4 is carried out in acetonitrile solvent, the intermediate III: the molar ratio of sodium iodide is 1 (1.0-1.5), the reaction temperature of the substitution reaction is 35-80 ℃, and the reaction time is 2-10 hours.
10. The process according to claim 1, wherein the deboc-protecting reaction is carried out in a dichloromethane solvent in the presence of a second acid, which is trifluoroacetic acid, the reaction temperature of the deboc-protecting reaction being 0-30 ℃ and the reaction time being 16-20 hours.
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