CN105985373A - New method for preparing (R)-1,2-di-fatty acid glycerol phosphatidyl glyceride - Google Patents
New method for preparing (R)-1,2-di-fatty acid glycerol phosphatidyl glyceride Download PDFInfo
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- CN105985373A CN105985373A CN201510167501.3A CN201510167501A CN105985373A CN 105985373 A CN105985373 A CN 105985373A CN 201510167501 A CN201510167501 A CN 201510167501A CN 105985373 A CN105985373 A CN 105985373A
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- 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
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Abstract
The invention discloses a preparing method for di-fatty acid glycerol phosphatidyl glyceride. The preparing method includes the steps that (S)-1,2-fatty glyceride serves as a raw material, and is reacted with 2-cyano ethyl diisopropyl chloro-amidophosphoric acid or di-(diisopropyl amino) (2-cyano ethyoxyl) phosphine and 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolame in sequence, then phosphate esteris generated under the condition of iodine oxidation, finally all protecting groups are removed under the ammonia water condition and the weak acid condition, and the (R)-1,2-di-fatty acid glycerol phosphatidyl glyceride is obtained. According to the method, the raw materials are low in cost and easy to obtain, the reaction conditions are mild, the steps are simple, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, particularly relate to one (R)-1, the preparation method of 2-difatty acid glycerophosphonolipid acyl glyceride.
Background technology
Phospholipid is biomembranous important component part, and its two longer hydrocarbon chains contained have lipotropy, and the phosphate radical contained has hydrophilic so that it is can form Guan Bi bilayer in aqueous medium, can be as matrix material in pharmaceuticals industry.Particularly (R)-1,2-difatty acid glycerophosphonolipid acyl glyceride type compound purity is high, and good stability has stronger oxidation resistance than natural phospholipid, it is highly suitable for preparing liposome, is interpolation adjuvant indispensable and ideal in liposomal pharmaceutical preparation.
At present; about (R)-1; the synthesis document report of 2-difatty acid glycerophosphonolipid acyl glyceride type compound is less; CN103864840 obtains (S)-1 with the oxidation of 3-propylene halide initiation material; 2-glycol-3-halogenopropane; sequentially passing through and stearic acid or stearoylketene halogen addition and introduce the phosphate group with protection group; slough after protection group with 2; 2-dimethyl-4-methanol-1; 3-dioxolanes occurs additive reaction to obtain (R)-1,2-distearoyl base phosphatidyl glycerol in anhydrous pyridine.There is route complexity in the method, step is tediously long and uses the shortcoming such as heavy metal or high toxicity oxidant, is not suitable for industrialized production.
Summary of the invention
It is an object of the invention to provide one (R)-1, the preparation method of 2-difatty acid glycerophosphonolipid acyl glyceride, the method is simple to operate, and reaction condition is gentle, is suitable for industrialized production.
Wherein, the method comprises the following steps:
(1) compound of formula I (S)-1,2-fatty glyceride and 2-cyano ethyl diisopropyl chloro phosphoramidic acid under the conditions of diisopropyl ethyl amine or with double (diisopropylaminoethyls) (2-cyanoethoxy) phosphine under the conditions of 5-ethylmercapto group tetrazole, obtaining Formula II compound, reaction equation is as follows:
Wherein, R represents R=CH3(CH2)n,
n = 6-20。
Wherein, reaction dissolvent is selected from anhydrous methylene chloride, anhydrous acetonitrile, DMF, N-Methyl pyrrolidone etc., preferably anhydrous methylene chloride；Reaction temperature is 0 150 DEG C, preferably 25 DEG C.
(2) by Formula II compound and 2,2-dimethyl-4-methylol-DOX tetrazole be catalyzed under, occur additive reaction, with after be oxidized to formula III phosphate compound through iodine.
Wherein, R represents R=CH3(CH2)n,
n = 6-20；
Wherein, the additive reaction solvent under tetrazole is catalyzed is selected from anhydrous acetonitrile, anhydrous methylene chloride, DMF, N-Methyl pyrrolidone etc., preferably anhydrous acetonitrile；Reaction temperature is 0-100 DEG C, preferably 25 DEG C；
Wherein, the solvent of iodine oxidation reaction is selected from oxolane, water and the mixed solvent of pyridine, and its proportional volume is than preferably 9:1:0.1.
(3) after first formula III compound being sloughed 2-cyano ethyl protection group under aqueous ammonia conditions, slough isopropylene protection base the most under mildly acidic conditions, obtain formula IV (R)-1,2-difatty acid glycerophosphonolipid acyl glyceride type compound.
Wherein, R represents R=CH3(CH2)n,
n = 6-20；
Wherein, the concentration of described ammonia is 10%-35%, preferably 30%；Reaction temperature is 30-100 DEG C, preferably 55 DEG C.
Wherein, described solutions of weak acidity is selected from acetic acid aqueous solution, dilute hydrochloric acid, p-methyl benzenesulfonic acid etc., preferably 30% acetic acid aqueous solution；Reaction temperature is 0-100 DEG C, preferably 25 DEG C.
Compared with prior art, the invention have the advantages that
1. with compound (S)-1,2-fatty glyceride is initiation material, and raw material is easy to get, and has good optical stability, it is easy to ensure the optical purity of subsequent products.
2. being respectively adopted 2-cyanoethanol and isopropylidene as blocking group, it is easy to slough, reaction condition is gentle.
3. the present invention uses 2-cyano ethyl diisopropyl chloro phosphoramidic acid or with double (diisopropylaminoethyls) (2-cyanoethoxy) phosphine as phosphorus source, two kinds of raw materials are the most cheap and easy to get, and reaction gentleness, it is convenient to introduce, compared to 3,4-veratryl silver phosphate or phosphorus oxychloride are more conducive to industrialization.
Accompanying drawing explanation
Fig. 1 is the reaction equation preparing difatty acid glycerophosphonolipid acyl glyceride in an embodiment of the present invention.
Detailed description of the invention
Describe the present invention below with reference to detailed description of the invention shown in the drawings.But these embodiments are not limiting as the present invention, structure, method or conversion functionally that those of ordinary skill in the art is made according to these embodiments are all contained in protection scope of the present invention.
Term used in the present invention, except as otherwise noted, typically has the implication that those of ordinary skill in the art are generally understood that.The various processes not described in detail and method are conventional methods as known in the art.
Embodiment 1.
(R) preparation (R=CH of-1,2-distearyl-[(2-cyanoethoxy)-(diisopropylaminoethyl)-phosphorus oxygen] glyceride3(CH2)16) (method one)
Under argon shield, by (S)-1,2-tristerin (0.62g, 1 mmol) is dissolved in 10 mL anhydrous methylene chlorides, after adding 1 mL diisopropylethylamine.At 0 DEG C, after dropping 2-cyano ethyl diisopropyl chloro phosphoramidic acid (0.43 mL, 2 mmol), it is warmed to room temperature reaction overnight.Add 10 mL saturated sodium bicarbonate aqueous solutions and terminate reaction, dichloromethane extracts, organic layer anhydrous sodium sulfate is dried, after concentration, crude product ethyl acetate-light petrol recrystallization obtains 0.62 g (R)-1,2-distearyl-[(2-cyanoethoxy)-(diisopropylaminoethyl)-phosphorus oxygen] glyceride, yield 75%.
Embodiment 2.
(R) preparation (R=CH of-1,2-distearyl-[(2-cyanoethoxy)-(diisopropylaminoethyl)-phosphorus oxygen] glyceride3(CH2)16) (method two)
Under argon shield; by (S)-1; 2-tristerin (0.62g; 1 mmol) it is dissolved in 10 mL anhydrous methylene chlorides; after adding 5-ethylmercapto group tetrazole (0.13g, 1 mmol), double (diisopropylaminoethyl) (2-cyanoethoxy) phosphine (0.24 g of dropping; after 1mmol), it is heated to back flow reaction overnight.Add 10 mL saturated sodium bicarbonate aqueous solutions and terminate reaction, dichloromethane extracts, organic layer anhydrous sodium sulfate is dried, after concentration, crude product obtains 0.57 g (R)-1 through ethyl acetate-light petrol recrystallization, 2-distearoyl-[(2-cyanoethoxy)-(diisopropylaminoethyl)-phosphorus oxygen] glyceride, yield 69%.
Embodiment 3.
(R) preparation (R=CH of-1,2-distearoyl-[(2-cyanoethoxy)-(2,2-dimethyl-1,3-dioxy-4-base) methoxyl group-] phosphatidyl glycerol ester3(CH2)16)
(R)-1,2-distearyl-[(2-cyanoethoxy)-(diisopropylaminoethyl)-phosphorus oxygen] glyceride (0.82 g, 1 mmol) in 10 mL anhydrous acetonitriles, subsequently by 2,2-dimethyl-4-methylol-1, anhydrous acetonitrile 15 mL of 3-dioxolanes (180 μ L, 1.5mmol) and 2.5% tetrazole (5 mL) is added drop-wise in above-mentioned solution, and reaction 1 hour is stirred at room temperature.It is concentrated to dryness, the oxolane of the iodine of 0.1 M-water-pyridine (9:1:0.1) mixed solution is joined in this concentrate, after stirring reaction 1 hour, it is concentrated to dryness, after adding chloroform, successively with sodium sulfite aqueous solution and saturated aqueous common salt washing, organic layer anhydrous sodium sulfate, after concentration, it is directly used in the next step.
Embodiment 4.
(R) preparation (R=CH of-1,2-glycerol disterate phosphatidylglycerol ester (DSPG)3(CH2)16)
Adding 20 mL strong aqua ammonia in above-mentioned concentrate, room temperature reaction, after 1 hour, is heated to 55 DEG C and reacts 1 hour, be concentrated to dryness；Being subsequently adding 30% acetic acid aqueous solution 10 mL, room temperature reaction, after 2 hours, is concentrated to dryness.Adding 80 mL chloroform extractions, after saturated aqueous common salt washs three times, organic layer anhydrous sodium sulfate is dried, and filtering and concentrating obtains crude product, purifies with column chromatography and obtains white powdery solids 0.49 g, two-step reaction total recovery 63%.1H-NMR (CDCl3, 300MHz) δ(ppm): 0.89 (t, 6H, J =
7.7 Hz), 1.32-1.57 (m, 60H), 2.26-2.40 (m, 4H), 3.70-3.74 (m, 2H), 3.78-3.85
(m, 2H), 4.15-4.18 (m, 1H), 4.28 (d, 2H, J = 7.0 Hz), 4.32-4.35(m, 1H),
4.50-4.53(m, 1H), 5.15-5.20 (m,1H). MS (ESI)m/e: 780.1[M+H]+, 778.1[M-H]-。
Embodiment 5.
(R) preparation (R=CH of-1,2-two palmitic acid phosphatidylglycerol ester3(CH2)14)
According to the method for embodiment 1-4, with (S)-1,2-tripalmitin replaces (S)-1, and 2-tristerin carries out above-mentioned reaction, obtains (R)-1,2-bis-palmitic acid phosphatidylglycerol ester.1H-NMR (CDCl3,
300MHz) δ(ppm): 0.89 (t, 6H, J =
7.7 Hz), 1.32-1.58(m, 56H), 2.27-2.41 (m, 4H), 3.69-3.74 (m, 2H), 3.78-3.86 (m,
2H), 4.15-4.18 (m, 1H), 4.29 (d, 2H, J = 7.0 Hz), 4.33-4.37(m, 1H),
4.50-4.56(m, 1H), 5.15-5.24 (m,1H). MS (ESI)m/e: 723.8[M+H]+, 721.8[M-H]-.
It is to be understood that, although this specification is been described by according to embodiment, but the most each embodiment only comprises an independent technical scheme, this narrating mode of description is only for clarity sake, those skilled in the art should be using description as an entirety, technical scheme in each embodiment can also form, through appropriately combined, other embodiments that it will be appreciated by those skilled in the art that.
The a series of detailed description of those listed above is only for illustrating of the feasibility embodiment of the present invention; they also are not used to limit the scope of the invention, and all equivalent implementations or changes made without departing from skill of the present invention spirit should be included within the scope of the present invention.
Claims (6)
1. prepare (R)-1, the new method of 2-difatty acid glycerophosphonolipid acyl glyceride, it is characterised in that comprise the steps: for one kind
(1) compound of formula I (S)-1,2-fatty glyceride and 2-cyano ethyl diisopropyl chloro phosphoramidic acid under the conditions of diisopropyl ethyl amine or with double (diisopropylaminoethyls) (2-cyanoethoxy) phosphine under the conditions of 5-ethylmercapto group tetrazole, obtaining Formula II compound, reaction equation is as follows:
Wherein R represent R=
CH3(CH2)n, n = 6-20。
(2) by Formula II compound and 2,2-dimethyl-4-methylol-DOX tetrazole be catalyzed under, occur additive reaction, with after be oxidized to formula III phosphate compound through iodine.
Wherein R represents R=CH3(CH2)n,
n = 6-20。
(3) after first formula III compound being sloughed 2-cyano ethyl protection group under aqueous ammonia conditions, slough isopropylene protection base the most under mildly acidic conditions, obtain formula IV (R)-1,2-difatty acid glycerophosphonolipid acyl glyceride type compound.
Wherein R represents R=CH3(CH2)n,
n = 6-20。
Preparation the most according to claim 1 (R)-1, the new method of 2-difatty acid glycerophosphonolipid acyl glyceride, it is characterized in that, reaction dissolvent described in step (1) is selected from anhydrous methylene chloride or anhydrous acetonitrile or N, dinethylformamide or N-Methyl pyrrolidone, reaction temperature is 0 150 DEG C.
Preparation the most according to claim 1 (R)-1, the new method of 2-difatty acid glycerophosphonolipid acyl glyceride, it is characterized in that, the reaction dissolvent under tetrazole is catalyzed described in step (2) is selected from anhydrous acetonitrile or anhydrous methylene chloride or DMF or N-Methyl pyrrolidone.
Preparation the most according to claim 1 (R)-1, the new method of 2-difatty acid glycerophosphonolipid acyl glyceride, it is characterized in that, the solvent of the iodine oxidation reaction described in step (2) is selected from oxolane or water and the mixed solvent of pyridine, and its proportional volume ratio is for 9:1:0.1.
Preparation the most according to claim 1 (R)-1, the new method of 2-difatty acid glycerophosphonolipid acyl glyceride, it is characterised in that described in step (3), the concentration of ammonia is 10%-35%, and reaction temperature is 30-100 DEG C.
Preparation the most according to claim 1 (R)-1, the new method of 2-difatty acid glycerophosphonolipid acyl glyceride, it is characterised in that step (3) described solutions of weak acidity is selected from acetic acid aqueous solution or dilute hydrochloric acid or p-methyl benzenesulfonic acid.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484667A (en) * | 2018-03-21 | 2018-09-04 | 江苏正大清江制药有限公司 | A kind of synthesis technology of noval chemical compound phosphatidyl 3- hydroxypropionitriles |
| CN111285899A (en) * | 2020-03-20 | 2020-06-16 | 华东师范大学 | Preparation method of di-saturated acyl phosphatidylethanolamine |
| CN113354679A (en) * | 2021-07-05 | 2021-09-07 | 南京恒远科技开发有限公司 | Preparation process of distearoyl phosphatidyl glycerol sodium |
| JP2021534076A (en) * | 2018-06-26 | 2021-12-09 | サインパス ファルマ, インク.Signpath Pharma, Inc. | New lipid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008011559A2 (en) * | 2006-07-20 | 2008-01-24 | University Of Rochester | Synthetic lung surfactant and use thereof |
| CN101874112A (en) * | 2006-07-31 | 2010-10-27 | 库瑞瓦格有限责任公司 | Nucleic acid of formula I): GlXmGn, or (II): ClXmCn, in particular as an immune-stimulating agent/adjuvant |
| CN102065901A (en) * | 2008-06-19 | 2011-05-18 | 日本新药株式会社 | Drug carrier |
| CN104306332A (en) * | 2014-09-24 | 2015-01-28 | 东南大学 | Camptothecin phospholipid compound, and medicinal composition and application thereof |
-
2015
- 2015-04-10 CN CN201510167501.3A patent/CN105985373A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008011559A2 (en) * | 2006-07-20 | 2008-01-24 | University Of Rochester | Synthetic lung surfactant and use thereof |
| CN101874112A (en) * | 2006-07-31 | 2010-10-27 | 库瑞瓦格有限责任公司 | Nucleic acid of formula I): GlXmGn, or (II): ClXmCn, in particular as an immune-stimulating agent/adjuvant |
| CN102065901A (en) * | 2008-06-19 | 2011-05-18 | 日本新药株式会社 | Drug carrier |
| CN104306332A (en) * | 2014-09-24 | 2015-01-28 | 东南大学 | Camptothecin phospholipid compound, and medicinal composition and application thereof |
Non-Patent Citations (6)
| Title |
|---|
| ILONA A. OLEYNIKOVA ET AL.，: ""Synthesis of Phospholipid-Ribavirin Conjugates"", 《HELVETICA CHIMICA ACTA》 * |
| ROBERT H. NOTTER ET AL.: "Synthesis and surface activity of diether-linked phosphoglycerols: Potential applications for exogenous lung surfactants", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| ROSA CHILLEMI ET AL.: "Oligonucleotides Conjugated to Natural Lipids: Synthesis of Phosphatidyl-Anchored Antisense Oligonucleotides", 《BIOCONJUGATE CHEM.》 * |
| SRINIVAS BURGULA ET AL.: "Total Synthesis of a Glycosylphosphatidylinositol Anchor of the Human Lymphocyte CD52 Antigen", 《CHEM. EUR. J.》 * |
| YUSHMA BHURRUTH-ALCOR ET AL.: "Novel phospholipid analogues of pan-PPAR activator tetradecylthioacetic acid are more PPARa selective", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 陈光友: ""磷脂酰胆碱、磷脂酰乙醇胺和磷脂酰甘油的全合成研究"", 《西北大学硕士学位论文》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484667A (en) * | 2018-03-21 | 2018-09-04 | 江苏正大清江制药有限公司 | A kind of synthesis technology of noval chemical compound phosphatidyl 3- hydroxypropionitriles |
| JP2021534076A (en) * | 2018-06-26 | 2021-12-09 | サインパス ファルマ, インク.Signpath Pharma, Inc. | New lipid |
| JP7325840B2 (en) | 2018-06-26 | 2023-08-15 | サインパス ファルマ，インク． | Novel lipid |
| CN111285899A (en) * | 2020-03-20 | 2020-06-16 | 华东师范大学 | Preparation method of di-saturated acyl phosphatidylethanolamine |
| CN111285899B (en) * | 2020-03-20 | 2022-10-04 | 华东师范大学 | Preparation method of di-saturated acyl phosphatidylethanolamine |
| CN113354679A (en) * | 2021-07-05 | 2021-09-07 | 南京恒远科技开发有限公司 | Preparation process of distearoyl phosphatidyl glycerol sodium |
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