CN103087090B - Synthetic method of 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine - Google Patents
Synthetic method of 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine Download PDFInfo
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- CN103087090B CN103087090B CN201210552270.4A CN201210552270A CN103087090B CN 103087090 B CN103087090 B CN 103087090B CN 201210552270 A CN201210552270 A CN 201210552270A CN 103087090 B CN103087090 B CN 103087090B
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Abstract
The invention provides a synthetic method of mifamurtide intermidate dipalmitoyl phosphoethanolamine. The method comprises the steps of: taking 2-phthalimide-phosphorodichloridate, and alpha, beta-glycerol-1,3-dipalmitate as raw materials; respectively dissolving by tetrahydrofuran and pyridine; taking the pyridine as alkali to carry out hydrolysis reaction during condensation reaction; directly filtering to obtain pure intermediate compound II; taking the tetrahydrofuran and ethanol as solvents, and carrying out deprotection by hydrazine hydrate to obtain the dipalmitoyl phosphoethanolamine. The method is simple and convenient to operate, rapid to react, and suitable for industrial production; and a reagent is saved.
Description
Technical field
The invention belongs to organic chemistry filed, relate to the synthetic method of rice lumbering peptide intermediate DPPE further.
Background technology
Rice lumbering peptidoliposome injection is IDM drugmaker product (trade(brand)name: Mepact), is used for the treatment of non-metastatic, resectable osteosarcoma.Drug fut1989,14, (3): 220 disclose rice lumbering peptide a kind of synthetic method, wherein synthetic route final step employs DPPE as synthetic intermediate.
DPPE (formula I) has following structural formula:
Molecular formula: C37H74NO8P
CAS：923-61-5
DPPE is not only synthesis rice lumbering peptide important intermediate; and be proved to be there is the senile dementia for the treatment of, heredity and nongenetic cerebrovascular disease, and treat that cerebration is slow, the potentiality of hypomnesis, the syndromes such as anxious state of mind and affective fragility.
The synthesis of phosphatidyl ethanolamine compounds has many sections of bibliographical informations, and method is mostly more complicated.Document " HelveticaChimicaActa; 1957; vol.40; p.1928-1931 " disclose by 2-phthalic imidine ethyl-dichlor-phosphoryl (compound III) and α; β-glycerol-1,3-dipalmitate (compound IV) is raw material; take trichloromethane as solvent; alkali is done with triethylamine; through condensation and hydrolysis; then extract, concentrated and recrystallization obtains midbody compound II, is then the method that water used in solvent closes that hydrazine deprotection obtains DPPE with ethanol.Its synthetic route is:
Find in research, disclosed in document, method is reacted, long reaction time, and impurity is more, and the aftertreatment of Compound II per is complicated, is not suitable for amplifying industrial production.
Summary of the invention
The invention provides the synthetic method of a kind of meter of lumbering peptide intermediate DPPE, the method is easy and simple to handle, is swift in response, and saves reagent, is applicable to suitability for industrialized production.
The synthetic method of a kind of DPPE provided by the invention, it is characterized in that comprising following steps: 1) condensation, hydrolysis: 2-phthalic imidine ethyl-dichlor-phosphoryl is added in reactor, add anhydrous tetrahydro furan to dissolve, separately get α, β-glycerol-1,3-dipalmitate, dissolve with anhydrous pyridine, the pyridine solution of α, β-glycerol-1,3-dipalmitate is added dropwise in above-mentioned reserve liquid by 0 ~ 20 DEG C, drips off and continues reaction 30 ~ 90 minutes; Adding dilute hydrochloric acid regulates pH to be 1 ~ 2, leaves standstill after stirring, and filters, filter cake water wash, dry;
2) Deprotection: step 1) add solvothermal in products obtained therefrom and dissolve; described solvent is ethanol and tetrahydrofuran (THF) mixed solvent; drip hydrazine hydrate; react 1 ~ 2 hour; adding dilute hydrochloric acid regulates pH to be 5 ~ 6, cooling crystallization, suction filtration; obtain crude product, obtain DPPE sterling with silica gel chromatography column purification.
Reaction scheme is:
Further optimization, step 1) condensation reaction thing α, the mol ratio of β-glycerol-1,3-dipalmitate and 2-phthalic imidine ethyl-dichlor-phosphoryl is 1: 1 ~ 4, preferably 1: 1.1 ~ 1.5; The mass volume ratio of 2-phthalic imidine ethyl-dichlor-phosphoryl and anhydrous tetrahydro furan is 1: 2 ~ 6, preferably 1: 2.5 ~ 4; α, β-glycerol-1,3-dipalmitate is 1: 2 ~ 10 with the mass volume ratio of anhydrous pyridine dissolved, preferably 1: 4 ~ 5; Temperature of reaction preferably 8 ~ 10 DEG C; Adjust ph can be unnecessary in neutralization reaction liquid pyridine, the preferred 6N of dilute hydrochloric acid concentration of employing, can reduce the liquor capacity after neutralization, handled easily.Above-mentioned anhydrous solvent can directly be buied by market, or is obtained by measure self-controls such as molecular sieve dryings.
Step 2) volume ratio of ethanol and tetrahydrofuran (THF) is 5: 2 in described ethanol and tetrahydrofuran (THF) mixed solvent, step 1) mass volume ratio of product and solvent is 1: 15 ~ 20.Described silica gel chromatography Column methods is first use the elutriant of methylene chloride/methanol (9: 1) polarity to rinse; the elutriant using methylene chloride/methanol/water (90: 18: 2) polarity after having been rushed by impurity instead rinses; collect elutriant concentrated removing organic solvent; then suction filtration, filtration cakes torrefaction obtains DPPE sterling.
The invention provides the synthetic method of a kind of meter of lumbering peptide intermediate DPPE; the method is with 2-phthalic imidine ethyl-dichlor-phosphoryl and α; β-glycerol-1,3-dipalmitate is raw material; use tetrahydrofuran (THF) and pyridinium dissolution respectively; while condensation reaction, pyridine carries out making hydrolysis reaction as alkali; then direct filtration just obtains purer midbody compound II; Compound II per for solvent, obtains DPPE with hydrazine hydrate deprotection with tetrahydrofuran (THF) and ethanol.The method compared with prior art, condensation hydrolysing step avoids and uses trichloromethane (easily poison-2 processed) to make solvent, pyridine had not only made solvent but also as alkali, condensation and hydrolysis reaction are carried out simultaneously, shorten the reaction times, and unexpected discovery after completion of the reaction, direct filtration reaction solution during aftertreatment, then just can obtain with water wash the intermediate II that purity is greater than 90%, and yield is higher than 80%, the extraction adopted with prior art, concentrated, the intermediate II aftertreatment purifying process of recrystallization is compared again, enormously simplify technique, cost-saving, raise the efficiency, be applicable to suitability for industrialized production.
Further combined with the embodiment of embodiment, the present invention will be further described below.
Embodiment
Embodiment one
The synthesis of intermediate II
Compound III (28.2g, 0.09mol) is added in reactor, adds anhydrous tetrahydro furan (80ml), stirring and dissolving, for subsequent use.Separately get a reactor, add the pyridine (200ml) that compound IV (40g, 0.07mol) and molecular sieve drying are crossed, be heated to 40 DEG C and make it entirely molten, be cooled to room temperature.In 8 DEG C of cryostats, the solution of compound IV is added dropwise in reserve liquid, drips off and continue reaction 35 minutes in 10 DEG C, react complete.Being added dropwise to 6N salt acid for adjusting pH value in 10 DEG C is 1 ~ 2, dropwises stirring 3 minutes, leaves standstill crystallization 3 hours.Filter, filter cake adds water and stirs and wash once, filters, obtains intermediate II 49.8g, purity 93.9%, yield 86.2% in 40 DEG C of oven dryings.
The synthesis of DPPE
Intermediate II (49.8g) adds in reactor, adds tetrahydrofuran (THF) (150ml) and dehydrated alcohol (750ml), is heated to 50 DEG C of stirring and dissolving.Be added dropwise to hydrazine hydrate (12g), react 1 ~ 2 hour, dripping 2N salt acid for adjusting pH value after answering is 5 ~ 6, is cooled to 20 DEG C of standing crystallizatioies.Suction filtration, filter cake adds proper amount of acetone drip washing, filtration cakes torrefaction.Cross silica column purification; the elutriant of methylene chloride/methanol (9: 1) polarity is first used to rinse; the elutriant using methylene chloride/methanol/water (90: 18: 2) polarity after having been rushed by impurity instead rinses; collect elutriant concentrated removing organic solvent; then suction filtration; filtration cakes torrefaction obtains two palmitoyl phosphatidylethanolamine 19g, purity 98.9%, yield 45.3%.
Embodiment two
The synthesis of intermediate II
Compound III (140g, 0.454mol) is added in reactor, adds anhydrous tetrahydro furan (400ml), stirring and dissolving, for subsequent use.Separately get a reactor, add the pyridine (800ml) that compound IV (200g, 0.35mol) and molecular sieve drying are crossed, be heated to 40 DEG C and make it entirely molten, be cooled to room temperature.In 10 DEG C of cryostats, the solution of compound IV is added dropwise in reserve liquid, drips off and continue reaction 70 minutes in 10 DEG C, react complete.Being added dropwise to 6N salt acid for adjusting pH value in 10 DEG C is 1 ~ 2, dropwises stirring 3 minutes, leaves standstill crystallization 2 hours.Filter, filter cake adds water and stirs and wash once, filters, obtains intermediate II 252.9g, purity 95.1%, yield 87.5% in 40 DEG C of oven dryings.
The synthesis of DPPE
Intermediate II adds in reactor, adds tetrahydrofuran (THF) (800ml) and dehydrated alcohol (2000ml), is heated to 50 DEG C of stirring and dissolving.Be added dropwise to hydrazine hydrate (57g), react 1 ~ 2 hour, dripping 2N salt acid for adjusting pH value after answering is 5 ~ 6, is cooled to 20 DEG C of standing crystallizatioies.Suction filtration, filter cake adds proper amount of acetone drip washing, filtration cakes torrefaction.Cross silica column purification; the elutriant of methylene chloride/methanol (9: 1) polarity is first used to rinse; the elutriant using methylene chloride/methanol/water (90: 18: 2) polarity after having been rushed by impurity instead rinses; collect elutriant concentrated removing organic solvent; then suction filtration; filtration cakes torrefaction obtains two palmitoyl phosphatidylethanolamine 102g, purity 98.9%, yield 47.9%.
DPPE detects data:
Fusing point: 183.8 ~ 186.8 DEG C
Specific optical rotation :+6.38 (chloroforms: acetic acid=9: 1, c=3)
1H NMR(CD
3OD/CDCl
3＝1∶1)：0.89(t，6H)，1.29(s，48H)，1.59-1.65(m，4H)，2.30-2.34(m，4H)，3.10(t，2H)，，3.99-4.21(m，5H)，4.6(dd，1H，J)，5.22-5.25(m，1H)；7.86-8.22(m，2H).
m/z：690.49(M-H)
-，1381.99(2M-H)
-
Comparative example one
The synthesis of intermediate II
Compound III (10g) and compound IV (5g) are joined in reactor, adds the pyridine (200ml) crossed by molecular sieve drying, stirring at room temperature.React complete.Being added dropwise to 1N salt acid for adjusting pH value in 10 DEG C is 1 ~ 2, dropwises stirring 3 minutes, leaves standstill crystallization 3 hours.Filter, filter cake adds water and stirs and wash once, filters, obtains intermediate II crude product 7.1g, purity 78.5% in 40 DEG C of oven dryings, crosses silica column purification, first uses the elutriant of DCM/MeOH=9: 1 polarity to rinse, use DCM/MeOH/H instead after having been rushed by impurity
2the elutriant of O=90: 18: 2 polarity rinses, and collect elutriant concentrated removing organic solvent, then suction filtration, filtration cakes torrefaction obtains intermediate II sterling 5g, purity 95.9%, yield 69.2%.
The synthesis of DPPE
Intermediate II adds in reactor, adds tetrahydrofuran (THF) (20ml) and dehydrated alcohol (50ml), is heated to 50 DEG C of stirring and dissolving.Be added dropwise to hydrazine hydrate (6.0g), react 1 ~ 2 hour, dripping 2N salt acid for adjusting pH value after answering is 5 ~ 6, is cooled to 20 DEG C of standing crystallizatioies.Suction filtration, filter cake adds proper amount of acetone drip washing, filtration cakes torrefaction.Cross silica column purification; the elutriant of methylene chloride/methanol (9: 1) polarity is first used to rinse; the elutriant using methylene chloride/methanol/water (90: 18: 2) polarity after having been rushed by impurity instead rinses; collect elutriant concentrated removing organic solvent; then suction filtration; filtration cakes torrefaction obtains two palmitoyl phosphatidylethanolamine 1.9g, purity 97.8%, yield 45.2%.
Comparative example two
The synthesis of intermediate II
Add in reactor by compound III (10g) and 20ml trichloromethane, stirring and dissolving is as for subsequent use, for subsequent use in 10 DEG C of cold hydrazines.Separately get a reactor, add compound IV (10g) and trichloromethane 50ml, be added dropwise to 6g triethylamine while stirring in 8 ~ 10 DEG C, the mixed solution obtained slowly is added dropwise in reserve liquid, drip off and continue reaction 2 days.Temperature is kept not to be added dropwise to 10ml water higher than 35 DEG C.Stratification, abandons aqueous phase, and organic phase is concentrated dry, and add 100ml ether, reflux stirs 2 hours, suction filtration, and filter cake uses dilute hydrochloric acid and water wash respectively, and dry, crude product recrystallizing methanol obtains intermediate II sterling 3.1g, purity 89.5%, yield 21.5%.
The synthesis of DPPE
Intermediate II adds in reactor, adds dehydrated alcohol (50ml), is heated to 50 DEG C of stirring and dissolving.Be added dropwise to hydrazine hydrate (3.2g), react 1 ~ 2 hour, dripping 2N salt acid for adjusting pH value after answering is 5 ~ 6, is cooled to 20 DEG C of standing crystallizatioies.Suction filtration, filter cake adds proper amount of acetone drip washing, filtration cakes torrefaction.Cross silica column purification; the elutriant of methylene chloride/methanol (9: 1) polarity is first used to rinse; the elutriant using methylene chloride/methanol/water (90: 18: 2) polarity after having been rushed by impurity instead rinses; collect elutriant concentrated removing organic solvent; then suction filtration; filtration cakes torrefaction obtains two palmitoyl phosphatidylethanolamine 1.2g, purity 97.5%, yield 44.6%.
Claims (8)
1. a synthetic method for DPPE, is characterized in that comprising following steps:
1) condensation, hydrolysis: 2-phthalic imidine ethyl-dichlor-phosphoryl is added in reactor, add anhydrous tetrahydro furan to dissolve, separately get α, β-glycerol-1,3-dipalmitate, dissolve with anhydrous pyridine, 0 ~ 20 DEG C by α, the pyridine solution of β-glycerol-1,3-dipalmitate is added dropwise in above-mentioned reserve liquid, wherein α, the mol ratio of β-glycerol-1,3-dipalmitate and 2-phthalic imidine ethyl-dichlor-phosphoryl is 1: 1 ~ 4, the mass volume ratio of 2-phthalic imidine ethyl-dichlor-phosphoryl and anhydrous tetrahydro furan is 1g: 2 ~ 6mL, α, β-glycerol-1,3-dipalmitate is 1g: 2 ~ 10mL with the mass volume ratio of the anhydrous pyridine dissolved, drip off and continue reaction 30 ~ 90 minutes, adding dilute hydrochloric acid regulates pH to be 1 ~ 2, leaves standstill after stirring, and filters, filter cake water wash, dry,
2) Deprotection: step 1) add solvothermal in products obtained therefrom and dissolve; described solvent is ethanol and tetrahydrofuran (THF) mixed solvent; drip hydrazine hydrate; react 1 ~ 2 hour; adding dilute hydrochloric acid regulates pH to be 5 ~ 6, cooling crystallization, suction filtration; obtain crude product, obtain DPPE sterling with silica gel chromatography column purification.
2. method according to claim 1, is characterized in that, step 1) mol ratio of α, β-glycerol-1,3-dipalmitate and 2-phthalic imidine ethyl-dichlor-phosphoryl is 1: 1.1 ~ 1.5.
3. method according to claim 1, it is characterized in that, step 1) mass volume ratio of 2-phthalic imidine ethyl-dichlor-phosphoryl and anhydrous tetrahydro furan is 1g: 2.5 ~ 4mL, α, β-glycerol-1,3-dipalmitate is 1g: 4 ~ 5mL with the mass volume ratio of the anhydrous pyridine dissolved.
4. method according to claim 1, is characterized in that step 1) temperature of reaction is 8 ~ 10 DEG C.
5. method according to claim 1, is characterized in that step 1) described dilute hydrochloric acid concentration is 6N.
6. method according to claim 1, is characterized in that step 2) volume ratio of ethanol and tetrahydrofuran (THF) is 5: 2 in described ethanol and tetrahydrofuran (THF) mixed solvent.
7. method according to claim 1, is characterized in that step 2) in step 1) mass volume ratio of products therefrom and solvent is 1g: 15 ~ 20mL.
8. method according to claim 1, it is characterized in that step 2) described silica gel chromatography Column methods be first with volume ratio be 9: 1 methylene chloride/methanol elutriant rinse, methylene chloride/methanol/water elution liquid flushing that volume ratio is 90: 18: 2 is used instead after having been rushed by impurity, collect elutriant concentrated removing organic solvent, then suction filtration, filtration cakes torrefaction.
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| CN110330524A (en) * | 2019-07-10 | 2019-10-15 | 安徽昊帆生物有限公司 | Bis- palmityl-SN- glycerol -3- phosphatidyl ethanolamine of 1,2- and preparation method thereof |
| CN114213458A (en) * | 2021-12-27 | 2022-03-22 | 硅羿科技（上海）有限公司 | Cyclobutylamine-terminated distearoyl phosphatidylcholine and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101270130A (en) * | 2007-03-22 | 2008-09-24 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing bi-axungia acyl-phosphatidylethanolamine |
| CN101805367A (en) * | 2010-04-01 | 2010-08-18 | 华东师范大学 | Method for synthesizing PE (Phosphatidyl Ethanolamine) |
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| US6936298B2 (en) * | 2000-04-13 | 2005-08-30 | Emory University | Antithrombogenic membrane mimetic compositions and methods |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101270130A (en) * | 2007-03-22 | 2008-09-24 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing bi-axungia acyl-phosphatidylethanolamine |
| CN101805367A (en) * | 2010-04-01 | 2010-08-18 | 华东师范大学 | Method for synthesizing PE (Phosphatidyl Ethanolamine) |
Non-Patent Citations (1)
| Title |
|---|
| "Zur synthese der Phosphatide. Eine neue Synthses der Kephaline;R. Hirt, et al.;《Helvetica Chimica Acta》;19571231;第40卷;第1928-1931页 * |
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