CN113999259A - Preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt - Google Patents
Preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt Download PDFInfo
- Publication number
- CN113999259A CN113999259A CN202111317660.9A CN202111317660A CN113999259A CN 113999259 A CN113999259 A CN 113999259A CN 202111317660 A CN202111317660 A CN 202111317660A CN 113999259 A CN113999259 A CN 113999259A
- Authority
- CN
- China
- Prior art keywords
- reaction
- boc
- ethanolamine
- sodium salt
- tetrazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 28
- 239000011734 sodium Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims abstract description 39
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 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 25
- 238000006467 substitution reaction Methods 0.000 claims abstract description 17
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 16
- 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 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 238000005954 phosphonylation reaction Methods 0.000 claims abstract description 14
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 13
- 235000009518 sodium iodide Nutrition 0.000 claims abstract description 13
- 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 12
- 239000002253 acid Substances 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- -1 (diisopropylamino) oxymethylphosphine Chemical compound 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 150000003536 tetrazoles Chemical group 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- 230000001590 oxidative effect Effects 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000002131 composite material Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
- 238000003786 synthesis reaction Methods 0.000 abstract description 15
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000004809 thin layer chromatography Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- 238000001035 drying Methods 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000012467 final product Substances 0.000 description 5
- 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 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- YFYBXOIQXOOUCI-UHFFFAOYSA-N n-[[di(propan-2-yl)amino]-methoxyphosphanyl]-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C(C)C)P(OC)N(C(C)C)C(C)C YFYBXOIQXOOUCI-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000013603 viral vector Substances 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 System
- 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
Abstract
The invention provides a preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt, which comprises the following steps: step S1, carrying out phosphonylation reaction on (R) -glycerol acetonide, phosphine reagent and Boc-ethanolamine to generate an intermediate I; step S2, carrying out substitution reaction on the intermediate I and sodium iodide to generate an intermediate II; and step S3, mixing the intermediate II with an acid solution to perform hydrolysis reaction to generate the (R) -glycerophosphoryl phosphatidyl-N-Boc ethanolamine sodium salt. The synthesis method of the (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt provided by the embodiment of the invention has the advantages of short synthesis route, mild conditions, high efficiency and easiness in industrial production.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation method of (R) -glycerophosphoryl phosphatidyl-N-Boc ethanolamine sodium salt.
Background
PE phospholipids are important components of LDL phospholipids and are the major components of certain brain and retinal membranes. Can also be used for treating liver parasitosis and novel targeted liposome, can reduce toxic and side effects due to high efficiency, and can be used as a drug carrier for clinical application. In recent years, PE has received much attention as a carrier for drug delivery systems, and non-viral vector mediated gene therapy has now entered into various clinical studies, and some PE can be used to synthesize positive liposomes, one of the most promising carriers. In addition, PE can also be used for preparing a novel sound-sensitive carrier, namely liposome bubbles and a targeting material, so that the development of a preparation method which is short in step and simple and convenient to operate has very important significance and market value.
The (R) -glycerolphosphinoyl-N-Boc ethanolamine sodium salt is an important intermediate for synthesizing PE phospholipids, and different fatty acids can be grafted on glycerol to obtain the required PE phospholipids.
There is no relevant literature report on the synthesis of (R) -glycerylphosphinoyl-N-Boc ethanolamine sodium salt, and only relevant literature reports the synthesis of its racemate (CN 112552336A, Shenzhen advanced technology research institute, Shengzonghai et al), and the following formula (1) shows the synthetic route. As shown in the following formula (1), the compound I is subjected to ring opening, then is esterified with ethanolamine to obtain a compound II, then is subjected to amino protection by using Boc under an alkaline condition, and finally is reacted with sodium bicarbonate to form a sodium salt.
The first step ring-opening reaction of the scheme has long time and needs heating, and the raw materials are not completely reacted, so the yield is low.
Disclosure of Invention
In view of this, the preparation method of the (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt has the advantages of mild reaction conditions, high reaction speed, high yield and controllable cost.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt according to the embodiment of the invention comprises the following steps:
step S1, carrying out phosphonylation reaction on (R) -glycerol acetonide, phosphine reagent and Boc-ethanolamine to generate an intermediate I, wherein the chemical structural formula of the intermediate I is shown as the formula (I);
step S2, carrying out substitution reaction on the intermediate I and sodium iodide to generate an intermediate II, wherein the chemical structural formula of the intermediate II is shown as the following formula (II);
and step S3, mixing the intermediate II with an acid solution to perform hydrolysis reaction to generate the (R) -glycerophosphoryl phosphatidyl-N-Boc ethanolamine sodium salt.
Further, in the step S1, the phosphonylation reaction is performed in a first solvent under the action of a catalyst and an oxidant, wherein the first solvent is dichloromethane, and the phosphine reagent is bis (diisopropylamino) oxymethylphosphine; the catalyst is tetrazole; the oxidant is m-chloroperoxybenzoic acid.
Furthermore, the molar ratio of the (R) -acetonide condensed glycerol to the phosphine reagent to the tetrazole to the Boc-ethanolamine to the oxidant is 1: 1.0-1.5: 1.0-1.2: 1.5-2.0.
Further, the step S1 includes:
step S11, dissolving (R) -glycerol acetonide and bis (diisopropylamino) oxymethyl phosphine in dichloromethane, adding tetrazole, and reacting for 1-2h in ice-water bath;
step S12, continuously adding Boc-ethanolamine and tetrazole into the reaction liquid, and continuously reacting for 1-2 h;
and step S13, adding m-chloroperoxybenzoic acid into the reaction solution, and reacting for 1-2h at 10-20 ℃ to obtain the intermediate I.
Further, in the step S2, the molar ratio of the intermediate I to sodium iodide is 1 (1.0-1.5), the substitution reaction is performed in acetone, the reaction temperature of the substitution reaction is 35-65 ℃, and the reaction time is 2-4 h.
Further, in the step S3, the acid is trifluoroacetic acid, acetic acid, or a mixture thereof.
Further, the reaction solvent used in the hydrolysis reaction is water, methanol, or a mixture thereof; the reaction temperature is 0-30 ℃, and the reaction time is 10-20 h.
After the phosphonylation reaction in step S1 is completed, the compound I is washed with an aqueous sodium sulfite solution, washed with an aqueous sodium bicarbonate solution, dried, evaporated to dryness, and purified by column chromatography, and then the purified intermediate I is introduced into step S2 to be reacted in the next step.
After the substitution reaction in step S2 is completed, the reaction mixture is filtered, evaporated to dryness, and recrystallized to purify the intermediate II, and then the purified intermediate II is introduced into step S3 to undergo the next reaction.
Further, in step S3, after the hydrolysis reaction is completed, the method further includes: the reaction solution was dried and evaporated to dryness.
The technical scheme of the invention at least has one of the following beneficial effects:
(1) according to the preparation method provided by the embodiment of the invention, simple (R) -glycerol acetonide is used as an initial raw material, and a final product, namely (R) -glycerolphosphinoacyl-N-Boc ethanolamine sodium salt, is obtained through phosphorylation, substitution and hydrolysis reactions, wherein the chirality of a compound in the reaction is not changed, the group migration is less, the synthetic route is short, the yield is higher, and the total yield can reach 62%;
(2) the invention does not use expensive reagent, thus reducing the production cost;
(3) the synthesis process of the invention has simple operation, mild and easily-controlled 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 clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs. The use of "first," "second," and similar terms in the present application do not denote any order, quantity, or importance, but rather the terms are used to distinguish one element from another. Also, the use of the terms "a" or "an" and the like do not denote a limitation of quantity, but rather denote the presence of at least one.
The production method according to the embodiment of the present invention is first specifically described below.
The preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt according to the embodiment of the invention comprises the following steps:
step S1, phosphono reaction of (R) -glycerol acetonide with phosphine reagent and Boc-ethanolamine to produce intermediate I.
Wherein the reaction formula is represented by the following formula (S1):
wherein I represents an intermediate I.
That is, first, (R) -glycerol acetonide was used as a starting material, and the starting material was subjected to phosphonylation with a phosphine reagent and Boc-ethanolamine to give an intermediate I.
Further, in the step S1, the phosphonylation reaction is performed in the first solvent under the action of the catalyst and the oxidant. That is, in order to promote the progress of the phosphonylation reaction, the phosphonylation reaction is carried out in a solvent, i.e., in a dissolved state, under the action of a catalyst and an oxidizing agent.
Preferably, the first solvent is dichloromethane and the phosphine reagent is bis (diisopropylamino) oxymethylphosphine; the catalyst is tetrazole; the oxidant is m-chloroperoxybenzoic acid. The phosphine reagent, the catalyst and the oxidant have low cost and high yield, and do not cause the chiral change of the compound.
Furthermore, the molar ratio of the (R) -acetonide condensed glycerol to the phosphine reagent to the tetrazole to the Boc-ethanolamine to the oxidant is 1: 1.0-1.5: 1.0-1.2: 1.5-2.0. That is, the use of a small excess of the catalyst, Boc-ethanolamine, and oxidant is advantageous in maintaining the chirality and improving the yield.
Still further, the step S1 may include:
step S11, dissolving (R) -glycerol acetonide and bis (diisopropylamino) oxymethyl phosphine in dichloromethane, adding tetrazole, and reacting for 1-2h in ice-water bath;
step S12, continuously adding Boc-ethanolamine and tetrazole into the reaction liquid, and continuously reacting for 1-2 h;
and step S13, adding m-chloroperoxybenzoic acid into the reaction solution, and reacting for 1-2h at 10-20 ℃ to obtain the intermediate I.
That is, the above-mentioned phosphonylation reaction is carried out stepwise. The phosphonylation reaction is carried out step by step, which is beneficial to controlling by-products and maintaining the chirality unchanged.
After the phosphonylation reaction in step S1 is completed, the compound I is washed with an aqueous sodium sulfite solution, washed with an aqueous sodium bicarbonate solution, dried, evaporated to dryness, and purified by column chromatography, and then the purified intermediate I is introduced into step S2 to be reacted in the next step. The purified intermediate is used for the next reaction, which is beneficial to controlling by-products, and the obtained intermediate II is easier to purify.
And step S2, carrying out substitution reaction on the intermediate I and sodium iodide to generate an intermediate II.
Wherein the reaction formula is represented by the following formula (S2):
that is, after the above intermediate I is obtained, substitution reaction is further performed using sodium iodide.
Further, in the step S2, the molar ratio of the intermediate I to sodium iodide is 1 (1.0-1.5), the substitution reaction is performed in acetone, the reaction temperature of the substitution reaction is 35-65 ℃, and the reaction time is 2-4 h. That is, the use of a slight excess of sodium iodide in the substitution reaction is advantageous in promoting the reaction and improving the yield. In addition, the method is favorable for promoting the substitution reaction under the heating condition, and the reaction rate and the yield are improved.
After the substitution reaction in step S2 is completed, the reaction mixture is filtered, evaporated to dryness, and recrystallized to purify the intermediate II, and then the purified intermediate II is introduced into step S3 to undergo the next reaction. The purification of the intermediate II can be realized by simple filtration, evaporation to dryness and recrystallization. And (3) carrying out hydrolysis reaction after purification, wherein on one hand, the obtained product is dried without further purification, and on the other hand, unnecessary impurities such as by-products and the like can be avoided.
And step S3, mixing the intermediate II with an acid solution to perform hydrolysis reaction to generate the (R) -glycerophosphoryl phosphatidyl-N-Boc ethanolamine sodium salt.
That is, after obtaining the intermediate II, the intermediate II is hydrolyzed in an acidic environment to obtain the target product (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt.
The reaction formula is represented by the following formula (S3):
further, in the step S3, for example, trifluoroacetic acid, acetic acid, or a mixture thereof may be used. These acids promote the hydrolysis reaction described above on the one hand and do not produce unwanted by-products on the other hand.
Further, the reaction solvent used in the hydrolysis reaction is water, methanol, or a mixture thereof; the reaction temperature is 0-30 ℃, and the reaction time is 10-20 h. That is, the hydrolysis reaction may be carried out in an aqueous solution of the acid or a methanol solution. The reaction can be carried out at normal temperature, the reaction condition is mild, and the cost is controllable.
Further, in step S3, after the hydrolysis reaction is completed, the method further includes: the reaction solution was dried and evaporated to dryness.
The production method of the present invention is described in further detail below with reference to specific examples.
Example 1
An intermediate I: synthesis of t-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate
1g of (R) -glycerol acetonide and 1.98g of bis (diisopropylamino) methoxyphosphine were dissolved in 10mL of Dichloromethane (DCM) and 0.53g of tetrazole was added under ice-water bath. The reaction temperature was 0 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 1 hour. 1.22g of Boc-ethanolamine and 0.53g of tetrazole were added, the reaction temperature was 10 ℃, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 1 hour. 2.30g mCPBA (85%) was added in an ice water bath, the reaction temperature was 18 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 0.5 h. 8mL of a saturated aqueous solution of sodium sulfite was added thereto, and the mixture was stirred for 10 min. The layers were separated and the DCM layer was washed twice with 8mL of saturated aqueous sodium bicarbonate solution. Separating, drying with anhydrous sodium sulfate, and evaporating to dryness. The compound I1.79 g is obtained by column purification, and the yield is 64%.
Example 2
An intermediate I: synthesis of t-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate
1g of (R) -glycerol acetonide and 2.38g of bis (diisopropylamino) methoxyphosphine were dissolved in 10mL of Dichloromethane (DCM) and 0.64g of tetrazole was added under ice-water bath. The reaction temperature was 0 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 1 hour. 1.46g of Boc-ethanolamine and 0.64g of tetrazole were added, the reaction temperature was 10 ℃, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 1 hour. 2.30g mCPBA (85%) was added in an ice water bath, the reaction temperature was 18 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 0.5 h. 8mL of a saturated aqueous solution of sodium sulfite was added thereto, and the mixture was stirred for 10 min. The layers were separated and the DCM layer was washed twice with 8mL of saturated aqueous sodium bicarbonate solution. Separating, drying with anhydrous sodium sulfate, and evaporating to dryness. The compound I2.13 g is obtained by column purification, and the yield is 76%.
Example 3
An intermediate I: synthesis of t-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate
1g of (R) -glycerol acetonide and 2.38g of bis (diisopropylamino) methoxyphosphine were dissolved in 10mL of Dichloromethane (DCM) and 0.64g of tetrazole was added under ice-water bath. The reaction temperature was 0 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 1 hour. 1.46g of Boc-ethanolamine and 0.64g of tetrazole were added, the reaction temperature was 10 ℃, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 1 hour. 2.77g mCPBA (85%) was added in an ice water bath, the reaction temperature was 18 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) for 0.5 h. 8mL of a saturated aqueous solution of sodium sulfite was added thereto, and the mixture was stirred for 10 min. The layers were separated and the DCM layer was washed twice with 8mL of saturated aqueous sodium bicarbonate solution. Separating, drying with anhydrous sodium sulfate, and evaporating to dryness. The compound I2.19 g is obtained by column purification, and the yield is 78%.
Example 4
Intermediate II: synthesis of sodium (R) -2- (tert-butoxycarbonyl) amino) ethyl ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) phosphonate
2g of tert-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate are dissolved in 20mL of acetone, and 0.81g of sodium iodide are added. The reaction temperature was 55 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) and reacted for 4 hours. Filtering, evaporating to dryness to obtain 1.68g of a compound II, wherein the yield is 82%.
Example 5
Intermediate II: synthesis of sodium (R) -2- (tert-butoxycarbonyl) amino) ethyl ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) phosphonate
2g of tert-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate are dissolved in 20mL of acetone, and 1.62g of sodium iodide are added. The reaction temperature was 60 ℃ and the progress of the reaction was monitored by Thin Layer Chromatography (TLC) and reacted for 4 hours. Filtering, evaporating to dryness to obtain 1.83g of a compound II, wherein the yield is 89%.
Example 6
Intermediate II: synthesis of sodium (R) -2- (tert-butoxycarbonyl) amino) ethyl ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) phosphonate
2g of tert-butyl (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy (methoxy) phosphino) methoxy) ethyl) carbamate are dissolved in 20mL of acetone, and 1.62g of sodium iodide are added. The reaction temperature is 55 ℃, and the reaction time is 2 h. Filtering, evaporating to dryness to obtain 1.87g of a compound II, wherein the yield is 91%.
Example 7
The final product: synthesis of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt
2g of sodium (R) -2- (tert-butoxycarbonyl) amino) ethyl ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) phosphonate was added to 20mL of methanol, and 1mL of trifluoroacetic acid was added. The reaction temperature is 10 ℃, and the reaction time is 20 h. Drying and evaporating to dryness to obtain 1.43g of white waxy solid with the yield of 80 percent.
Example 8
The final product: synthesis of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt
2g of sodium (R) -2- (tert-butoxycarbonyl) amino) ethyl ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) phosphonate was added to 20mL of 50% aqueous acetic acid solution. The reaction temperature is 10 ℃, and the reaction time is 20 h. Drying and evaporating to dryness to obtain 1.43g of white waxy solid with the yield of 81 percent.
Example 9
The final product: synthesis of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt
2g of sodium (R) -2- (tert-butoxycarbonyl) amino) ethyl ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) phosphonate was added to 20mL of 70% aqueous acetic acid solution. The reaction temperature is 10 ℃, and the reaction time is 20 h. Drying, evaporating to dryness, and drying with toluene to obtain 1.49g of white waxy solid with yield of 83%.
Example 10
The final product: synthesis of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt
2g of sodium (R) -2- (tert-butoxycarbonyl) amino) ethyl ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) phosphonate was added to 20mL of 70% aqueous acetic acid solution. The reaction temperature is 30 ℃ and the reaction time is 16 h. Drying, evaporating to dryness, and drying with toluene to obtain white waxy solid 1.54g with yield of 86%.
As can be seen from the above analysis, the yield is higher when the excess phosphine reagent is used in the phosphonylation reaction, and the cost is increased when the amount of the oxidizing agent is too large; in the process of forming sodium salt, excessive sodium iodide is added to enable the reaction to be more sufficient, and the reaction can be faster by heating; the hydrolysis reaction is carried out more fully by using an acetic acid water system than a hydrochloric acid system, and the hydrolysis speed can be accelerated by heating.
From the above, the synthesis method of the (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt has the advantages of short synthesis route, mild conditions, high efficiency and easy industrial production.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. A preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt is characterized by comprising the following steps:
step S1, carrying out phosphonylation reaction on (R) -glycerol acetonide, phosphine reagent and Boc-ethanolamine to generate an intermediate I, wherein the chemical structural formula of the intermediate I is shown as the formula (I);
step S2, carrying out substitution reaction on the intermediate I and sodium iodide to generate an intermediate II, wherein the chemical structural formula of the intermediate II is shown as the following formula (II);
and step S3, mixing the intermediate II with an acid solution to perform hydrolysis reaction to generate the (R) -glycerophosphoryl phosphatidyl-N-Boc ethanolamine sodium salt.
2. The method according to claim 1, wherein in step S1, the phosphonylation reaction is performed in a first solvent under the action of a catalyst and an oxidant, wherein the first solvent is dichloromethane, and the phosphine reagent is bis (diisopropylamino) oxymethylphosphine; the catalyst is tetrazole; the oxidant is m-chloroperoxybenzoic acid.
3. The preparation method of claim 2, wherein the molar ratio of the (R) -acetonide glycerol to the phosphine reagent to the tetrazole, the Boc-ethanolamine to the oxidant is 1: 1.0-1.5: 1.0-1.2: 1.5-2.0.
4. The method for preparing a composite material according to claim 3, wherein the step S1 includes:
step S11, dissolving (R) -glycerol acetonide and bis (diisopropylamino) oxymethyl phosphine in dichloromethane, adding tetrazole, and reacting for 1-2h in ice-water bath;
step S12, continuously adding Boc-ethanolamine and tetrazole into the reaction liquid, and continuously reacting for 1-2 h;
and step S13, adding m-chloroperoxybenzoic acid into the reaction solution, and reacting for 1-2h at 10-20 ℃ to obtain the intermediate I.
5. The preparation method according to claim 1, wherein in the step S2, the molar ratio of the intermediate I to the sodium iodide is 1 (1.0-1.5), the substitution reaction is carried out in acetone, the reaction temperature of the substitution reaction is 35-65 ℃, and the reaction time is 2-4 h.
6. The method according to claim 1, wherein in step S3, the acid is trifluoroacetic acid, acetic acid, or a mixture thereof.
7. The method according to claim 6, wherein the reaction solvent used in the hydrolysis reaction is water, methanol, or a mixture thereof; the reaction temperature is 0-30 ℃, and the reaction time is 10-20 h.
8. The process according to claim 1, wherein after the phosphonoation reaction in step S1, the compound I is washed with an aqueous sodium sulfite solution, washed with an aqueous sodium bicarbonate solution, dried, evaporated to dryness, and purified by column chromatography, and the purified intermediate I is then introduced into step S2 for the next reaction.
9. The process according to claim 1, wherein the substitution reaction in step S2 is completed, followed by filtration, evaporation to dryness, recrystallization and purification, and thereafter the purified intermediate II is introduced into step S3 to be reacted in the next step.
10. The method as claimed in claim 1, wherein the step S3 further comprises, after the hydrolysis reaction is completed: the reaction solution was dried and evaporated to dryness.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111317660.9A CN113999259A (en) | 2021-11-09 | 2021-11-09 | Preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111317660.9A CN113999259A (en) | 2021-11-09 | 2021-11-09 | Preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113999259A true CN113999259A (en) | 2022-02-01 |
Family
ID=79928273
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111317660.9A Pending CN113999259A (en) | 2021-11-09 | 2021-11-09 | Preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113999259A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111285899A (en) * | 2020-03-20 | 2020-06-16 | 华东师范大学 | Preparation method of di-saturated acyl phosphatidylethanolamine |
-
2021
- 2021-11-09 CN CN202111317660.9A patent/CN113999259A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111285899A (en) * | 2020-03-20 | 2020-06-16 | 华东师范大学 | Preparation method of di-saturated acyl phosphatidylethanolamine |
Non-Patent Citations (2)
| Title |
|---|
| KAZUO MURAKAMI 等: "An Efficient Synthesis of Unsymmetrical Optically Active Phosphatidyl Glycerol", J. ORG. CHEM., 5 January 1999 (1999-01-05), pages 648 - 651 * |
| L. LEBEAU 等: "Synthesis of phospholipids linked to steroid hormone derivatives", CHEMISTRY AND PHYSICS OF LIPIDS, 31 December 1988 (1988-12-31), pages 57 - 62, XP024783481, DOI: 10.1016/0009-3084(88)90114-4 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104558035B (en) | A kind of purification process of tenofovir prodrug | |
| CN101805369B (en) | Preparation methods of distearoyl phosphatidyl ethanolamine and amino polyethylene glycol derivatives thereof | |
| CN111285899A (en) | Preparation method of di-saturated acyl phosphatidylethanolamine | |
| CN102060723A (en) | Preparation method of cationic liposome nanoparticles of amino acid | |
| CN113999259A (en) | Preparation method of (R) -glycerolphosphinyl-N-Boc ethanolamine sodium salt | |
| CN109824725B (en) | Preparation method of 4-phosphate-2H-chromene derivative | |
| CN115028670B (en) | Preparation method of N-acetyl-D-galactosamine trimer precursor | |
| CN114539343B (en) | Preparation method of glycocholic acid | |
| CN101610999A (en) | The hydrosulphite purification process of alpha-keto amide | |
| CN114014863B (en) | Preparation method of bone marrow protective agent traasiril | |
| CN106543018A (en) | The method for preparing scheme for lacosamide | |
| WO2007100086A1 (en) | Ligand, method for producing the same, and catalyst using the ligand | |
| CN112225753A (en) | Preparation method of (R) -1, 2-di-fatty acyl-sn-glycerol-3-phosphoric acid | |
| CN107629039B (en) | The preparation method and intermediate of deuterated acrylamide | |
| CN117143145A (en) | Preparation method of dioleoyl phosphatidylethanolamine | |
| CN114853806B (en) | Preparation method of 1, 2-dioleoyl-SN-glycerinum-3-phosphorylethanolamine | |
| CN112979695B (en) | Method for preparing 1, 2-di-fatty acyl-sn-glycerol-3-phosphatidylserine | |
| CN114591361B (en) | Preparation method of (R) -glycerophosphatidylethanolamine | |
| CN104926704A (en) | Nitrogen heterocyclic propane compound and preparation method thereof | |
| CN109384814B (en) | Purification method of novel tenofovir prodrug | |
| KR100219994B1 (en) | Glyceraldehyde-3-pentanide and process for producing same | |
| CN111138293B (en) | Method for synthesizing ibutilide fumarate intermediate by using microchannel reactor | |
| CN1217338A (en) | Process for synthesizing long-acting rapin lactones | |
| CN113651715B (en) | Method for synthesizing coumaroyl dopamine by one-pot method | |
| CN112794810B (en) | Synthesis method of cyclobutylamine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |