CN107200841B - A kind of synthetic method of trainingization diacylglycerol - Google Patents
A kind of synthetic method of trainingization diacylglycerol Download PDFInfo
- Publication number
- CN107200841B CN107200841B CN201610153716.4A CN201610153716A CN107200841B CN 107200841 B CN107200841 B CN 107200841B CN 201610153716 A CN201610153716 A CN 201610153716A CN 107200841 B CN107200841 B CN 107200841B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- organic base
- solvent
- diacylglycerol
- 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.)
- Expired - Fee Related
Links
- 150000001982 diacylglycerols Chemical class 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 150000007530 organic bases Chemical class 0.000 claims abstract description 14
- 239000012190 activator Substances 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000012048 reactive intermediate Substances 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 83
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 238000005360 mashing Methods 0.000 claims description 10
- FHLXUWOHGKLDNF-UHFFFAOYSA-N (2-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=CC=C1OC(Cl)=O FHLXUWOHGKLDNF-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- MSKSQCLPULZWNO-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanamine Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN MSKSQCLPULZWNO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000037452 priming Effects 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims 1
- 230000004913 activation Effects 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 230000003213 activating effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 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 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 229920001427 mPEG Polymers 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 22
- -1 pentadecane-p-nitrophenyl oxygen Chemical compound 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 14
- 125000002252 acyl group Chemical group 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000005119 centrifugation Methods 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 239000002808 molecular sieve Substances 0.000 description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 9
- 239000012265 solid product Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000005457 ice water Substances 0.000 description 5
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- CPZHJYJSCCEDQX-UHFFFAOYSA-N [O]C1=CC=C([N+]([O-])=O)C=C1 Chemical compound [O]C1=CC=C([N+]([O-])=O)C=C1 CPZHJYJSCCEDQX-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- OUHVPTUNAKUCJX-UHFFFAOYSA-N N1=CC=CC=C1.CN(C=1C=CNC1)C Chemical compound N1=CC=CC=C1.CN(C=1C=CNC1)C OUHVPTUNAKUCJX-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate group Chemical group C(C=C)(=O)[O-] NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- CHTAZMKEXNOPNA-UHFFFAOYSA-N azane;pyridin-1-ium;chloride Chemical class N.[Cl-].C1=CC=[NH+]C=C1 CHTAZMKEXNOPNA-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
- C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a kind of methods for synthesizing trainingization diacylglycerol, with the hydroxyl in activator activating compounds formula (I), formation reactive intermediate, that is, compound formula (II) is spare, then, under the conditions of solvent and organic base, compound II and mPEG-NH2Form carbamate structures, i.e. synthesising target compound formula (III).Synthetic route of the present invention is brief, easy to operate, favorable reproducibility, high income, easy to industrialized production.
Description
Technical field
The present invention relates to technical field of compound preparation, the in particular to field of Antibody Production Techniques containing polyethyleneglycol lipid, tools
Body is related to a kind of method and intermediate for synthesizing trainingization diacylglycerol.
Background technique
Trainingization diacylglycerol is a kind of typical PEG- lipid, and there are many PEG class drugs to be used for various disease for many years
Treatment.Such as based on siRNA design drug possess potential therapeutic effect in terms of many diseases, still, they due to
The high molecular weight of its own and polyanion center and curative effect cannot be played by being passively conveyed into cytoplasm, therefore, it
Needed in vivo by a complicated transportation system.And trainingization diacylglycerol is proved to may be used as traditional small-molecule drug
Transportation system, trainingization diacylglycerol can be self-assembled into the nanometer of macromolecular by the electrostatic interaction with polyanionic nucleic acid
Grain is to encapsulate siRNA.This system is proved to hold out broad prospects in terms for the treatment of.
Have no that related trainingization diacylglycerol product is sold on domestic market, and external customization price is extremely expensive, this
It is the bottleneck of current domestic nanometer formulation development.Synthetic method in relation to trainingization diacylglycerol is rarely reported, and only one at present
The document of patent (EP2119738A1) and the synthesis of some PEG- liposome derivatives in relation to mPEG (2000)-DMG synthesis, but
It is these route poor reproducibilities, we attempt to repeat method reported in the literature, but many experiments do not obtain target product.
Summary of the invention
Present invention aims at provide a kind of side for synthesizing trainingization diacylglycerol for the problems and shortcomings present on
Method, this method have many advantages, such as brief synthetic route, easy to operate, at low cost, high income, easy to industrialized production.
To achieve the goals above, the invention proposes a kind of new method for synthesizing trainingization diacylglycerol, the method packets
Include the following steps:
A. the hydroxyl in suitable activator activating compounds formula (I) is selected, is reacted under the conditions of solvent, organic base, shape
Viability intermediate, that is, compound formula (II) is spare；
B. suitable solvent and organic base is selected to make compound formula (II) and mPEG-NH2Carbamate structures are formed, i.e.,
Synthesising target compound formula (III).
The reaction route of the method are as follows:
Wherein, n=12~15；M=22~45.
Preferably, m=22,45；N=12,13,14,15.
Preferably, the specific reaction of the method are as follows:
Preferably, compound formula (I) includes: Formula (Ia), Formula (Ib), Formula (Ic), compound
Formula (Id), etc..
Preferably, compound formula (II) includes: that 14 two acyls of carbon of Formula (IIa) i.e.-p-nitrophenyl oxygen formoxyl-is sweet
Oil, Formula (IIb) i.e. two acyls of pentadecane-p-nitrophenyl oxygen formoxyl-glycerol, two acyl of Formula (IIc) i.e. 16 carbon-
17 two acyls of carbon of p-nitrophenyl oxygen formoxyl-glycerol, Formula (IId) i.e.-p-nitrophenyl oxygen formoxyl-glycerol, etc..
Preferably, compound formula (III) includes: Formula (IIIa) i.e. (1000)-ten four carbon diacylglycerol of mPEG, changes
Close object formula (IIIb) i.e. mPEG (1000)-pentadecane diacylglycerol, Formula (IIIc) i.e. two acyl of (1000)-ten six carbon of mPEG
Glycerol, Formula (IIId) i.e. (1000)-ten seven carbon diacylglycerol of mPEG, Formula (IIIe) i.e. mPEG (2000)-ten
Four carbon diacylglycerols, Formula (IIIf) i.e. mPEG (2000)-pentadecane diacylglycerol, Formula (IIIg) i.e. mPEG
(2000)-ten six carbon diacylglycerols, Formula (IIIh) i.e. (2000)-ten seven carbon diacylglycerol of mPEG, etc..
In the step a, preferably, the activator is to nitro phenyl chloroformate.
In the step a, the solvent is aprotic solvent comprising methylene chloride, chloroform, toluene, tetrahydrofuran, two
Chloroethanes or DMF.Preferably, solvent is methylene chloride.
In the step a, the organic base is pyridine, triethylamine or diisopropylethylamine.The reaction temperature be 0~
25 DEG C, the reaction time is 0.5~1.5h.
Wherein, the ratio between the compound formula (I), mole of the activator, the alkali be 1~1.2:1.5~3:2~
3.Preferably, the compound formula (I), to the ratio between mole of nitro phenyl chloroformate, pyridine be 1:1.5:2.
Preferably, after the completion of the priming reaction, still further comprising step in step a: being washed with cold saturated ammonium chloride
Pyridine in dereaction liquid, then be extracted with dichloromethane, it washes, dry, being evaporated, column chromatography.Eluant, eluent in column chromatography procedure
Mixture including ethyl acetate, petroleum ether or above-mentioned solvent.
Preferably, the compound formula (II) is dissolved in methylene chloride in the step b, the alkali is 4- bis-
Methylamino pyridine (DMAP), the reaction temperature are 0~25 DEG C, and the reaction time is 5~6 hours.
Preferably, in the step b, the compound formula (II), the mPEG-NH2, the organic base mole it
Than for 1.5~2:1:1.
In the step b, the solvent is aprotic solvent comprising methylene chloride, chloroform, toluene, tetrahydrofuran, two
Chloroethanes, N,N-dimethylformamide；The organic base includes pyridine, triethylamine, diisopropylethylamine or 4- dimethylamino pyrrole
Pyridine (DMAP).
Preferably, after the reaction terminates, still further comprising step in the step b: being washed away instead with dilute hydrochloric acid
The organic base in liquid is answered, then is extracted with dichloromethane, washes, dry, be evaporated, be beaten.
In the present invention, raw material diacylglycerol (being indicated below with compound formula (I)) can be according to existing document (Organic
Letters2007Vol.9, No.2 323-326) easily synthesize.
Beneficial effect of the present invention includes the following: the diacylglycerol (compound I) of the invention for using carbon chain lengths different for original
Material has used the activator that do not reported to carry out activated hydroxyl groups to nitro phenyl chloroformate, again with polyoxamide formation amino first
Acrylate structure, the different compound trainingization diacylglycerol of synthesis carbon chain lengths.Synthetic route of the present invention is brief, and the reaction time is short,
High income, total recovery is up to 75%~85%.(EP2119738A1) in the prior art, the reaction time be 12~for 24 hours, yield is only
It is 30% or so.The present invention is not related to the use of expensive reagent, reduces costs；Synthetic method of the present invention is easy to operate, condition
It is easily-controllable, be easy to large-scale production.
The midbody compound that do not reported, i.e. compound formula (II) are also disclosed in the present invention, wherein n=
12~15.
Preferably, compound formula (II) includes: that 14 two acyls of carbon of Formula (IIa) i.e.-p-nitrophenyl oxygen formoxyl-is sweet
Oil, Formula (IIb) i.e. two acyls of pentadecane-p-nitrophenyl oxygen formoxyl-glycerol, two acyl of Formula (IIc) i.e. 16 carbon-
17 two acyls of carbon of p-nitrophenyl oxygen formoxyl-glycerol, Formula (IId) i.e.-p-nitrophenyl oxygen formoxyl-glycerol, etc..
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail, and of the invention protects content not limit to
In following embodiment.Without departing from the spirit and scope of the invention, those skilled in the art it is conceivable that variation and excellent
Point is all included in the present invention, and using appended claims as protection scope.Implement process of the invention, condition,
Reagent, experimental method etc. are among the general principles and common general knowledge in the art, this hair in addition to what is specifically mentioned below
It is bright that there are no special restrictions to content.In order to be more clearly understood that technology contents of the invention, furtherly now in conjunction with embodiment
It is bright as follows:
Embodiment 1
Compound IIa i.e. 14 two acyls of carbon-p-nitrophenyl oxygen formoxyl-glycerol preparation
1024mg compound Ia (1eq) and 602mg is dissolved in 15mL to nitro phenyl chloroformate (1.5eq) under ice-water bath
Methylene chloride in, the pyridine of 0.46mL (3eq) is slowly added dropwise, restores to room temperature.After half an hour, TLC detection has been reacted
Entirely.The pyridine in reaction solution first is washed away with saturated ammonium chloride solution, organic phase is extracted with DCM (20mL × 3), merges organic phase,
Use Na2SO4After drying, is rotated and is done with Rotary Evaporators, obtain yellowish crude product, then cross column with petroleum ether and ethyl acetate gradient,
Obtain pure white solid i.e. compound IIa, 1192mg.Yield 98%.
1H NMR(400MHz,CDCl3): δ 8.29 (d, J=9.2Hz, 2H), 7.39 (d, J=9.2Hz, 2H), 5.46-
5.32 (m, 1H), 4.37 (d, J=11.6Hz, 4H), 2.35 (dt, J=9.6,7.6Hz, 4H), 1.63 (d, J=6.7Hz, 4H),
1.38-1.18 (m, 40H), 0.88 (t, J=6.8Hz, 6H)
MS (ESI): m/z=678.45 [M+H]+。
2 compound IIb of embodiment, that is, two acyls of pentadecane-p-nitrophenyl oxygen formoxyl-glycerol preparation
540mg compound Ib (1eq) and 401mg is dissolved in 15mL to nitro phenyl chloroformate (2eq) by ice-water bath condition
Solvent chloroform in, 10min is stirred under the conditions of ice-water bath, then slowly be added dropwise 0.415mL (3eq) triethylamine, slowly restore to
Room temperature.After half an hour, TLC detects fully reacting.The pyridine in reaction solution first is washed away with saturated ammonium chloride solution, with DCM (20mL
× 3) organic phase is extracted, merges organic phase, uses Na2SO4After drying, is rotated and done with Rotary Evaporators, obtain yellowish crude product, then
Column is crossed with petroleum ether and ethyl acetate gradient, obtains pure white solid i.e. compound IIb, 635mg.Yield 90%.
1H NMR(400MHz,CDCl3): δ 8.29 (d, J=9.2Hz, 2H), 7.39 (d, J=9.2Hz, 2H), 5.46-
5.32 (m, 1H), 4.25-4.5 (d, J=11.6Hz, 4H), 2.35 (d, J=9.6,7.6Hz, 4H), 1.66 (d, J=6.7Hz,
4H), 1.38-1.26 (m, 44H), 0.88 (t, J=6.8Hz, 6H)
MS (ESI): m/z=706.48 [M+H]+。
3 compound IIc of embodiment i.e. 16 two acyls of carbon-p-nitrophenyl oxygen formoxyl-glycerol preparation
1136mg compound Ic (1eq) and 600mg is dissolved in nitro phenyl chloroformate (1.5eq) under the conditions of ice-water bath
In the methylene chloride of 15mL, the pyridine of 0.46mL (3eq) is added dropwise, restores to room temperature.After half an hour, TLC detection has been reacted
Entirely.The pyridine in reaction solution first is washed away with saturated ammonium chloride solution, organic phase is extracted with DCM (20mL × 3), merges organic phase,
Use Na2SO4After drying, is rotated and is done with Rotary Evaporators, obtain yellowish crude product, then cross column with petroleum ether and ethyl acetate gradient,
Obtain pure white solid i.e. compound IIc, 1350mg.Yield 92%.
1H NMR(400MHz,CDCl3): δ 8.29 (d, J=9.2Hz, 2H), 7.39 (d, J=9.2Hz, 2H), 5.46-
5.32 (m, 1H), 4.37 (d, J=11.6Hz, 4H), 2.35 (dt, J=9.6,7.6Hz, 4H), 1.63 (d, J=6.7Hz, 4H),
1.38-1.18 (m, 48H), 0.88 (t, J=6.8Hz, 6H)
MS (ESI): m/z=734.51 [M+H]+。
4 compound IId of embodiment i.e. 17 two acyls of carbon-p-nitrophenyl oxygen formoxyl-glycerol preparation
596mg compound Id (1eq) and 301mg is dissolved in nitro phenyl chloroformate (1.5eq) under the conditions of ice-water bath
In the methylene chloride of 15mL, then the pyridine of 0.23mL (3eq) is slowly added dropwise, restores to room temperature.After half an hour, TLC detection
Fully reacting.The pyridine in reaction solution first is washed away with saturated ammonium chloride solution, organic phase is extracted with DCM (20mL × 3), is associated with
Machine phase, uses Na2SO4It after drying, is rotated with Rotary Evaporators dry, obtains yellowish crude product, then with petroleum ether and ethyl acetate gradient
Column is crossed, pure white solid i.e. compound IId, 663mg is obtained.Yield 87%.
1H NMR(400MHz,CDCl3): δ 8.29 (d, J=9.2Hz, 2H), 7.39 (d, J=9.2Hz, 2H), 5.46-
5.32 (m, 1H), 4.37-4.15 (d, J=11.6Hz, 4H), 2.32 (dt, J=9.6,7.6Hz, 4H), 1.63 (d, J=
6.7Hz, 4H), 1.38-1.18 (m, 52H), 0.88 (t, J=6.8Hz, 6H)
MS (ESI): m/z=762.54 [M+H]+。
Embodiment 5
The preparation of (1000)-ten four carbon diacylglycerol of 5.1 compound IIIa, that is, mPEG
Compound IIa (100mg, 1.5eq) and mPEG (1000)-NH are taken at room temperature2(100mg, 1eq) is dissolved in molecular sieve
In dried solvent 20mL DCM, the DMAP (1eq) of 12mg is added.After reacting 6h, after TLC detects fully reacting, reaction
Liquid is washed with 2mol/L dilute hydrochloric acid, then extracts (20mL × 3) with DCM, merges organic phase, with anhydrous sodium sulfate it is dry after, with true
Empty Rotary Evaporators are rotated to doing, and obtain crude product.Crude product finally obtains purity using ether mashing (3mL × 3), centrifugation
For 97% white solid product, i.e. compound IIIa 112mg, yield 70%.
1H NMR(400MHz,CDCl3): δ 5.85 (m, 1H), 4.42-4.19 (m, 4H), 3.68 (d, J=107.7Hz,
88H),3.38(s,3H),3.29(s,2H),2.35-2.32(s,4H),1.73(s,2H),1.66(s,4H),1.26(m,44H),
0.87 (d, J=6.5Hz, 6H)
MS (ESI): m/z=1597.08 [M+H]+。
The preparation of (1000)-ten four carbon diacylglycerol of 5.2 compound IIIa, that is, mPEG
Compound IIa (133mg, 2eq) and mPEG (1000)-NH are taken at room temperature2It is dry that (100mg, 1eq) is dissolved in molecular sieve
In the solvent 20mL DCM of dry mistake, the DMAP (1eq) of 12mg is added.After reacting 6h, after TLC detects fully reacting, reaction solution
It is washed with 2mol/L dilute hydrochloric acid, then extracts (20mL × 3) with DCM, merge organic phase, after anhydrous sodium sulfate drying, use vacuum
Rotary Evaporators are rotated to doing, and obtain crude product.Crude product is using ether mashing (3mL × 3), and centrifugation, finally obtaining purity is
96% white solid product, i.e. compound IIIa 125mg, yield 85%.
The preparation of 6 compound IIIb, that is, mPEG (1000) of embodiment-pentadecane diacylglycerol
Compound IIb (140mg, 2eq) and mPEG (1000)-NH are taken at room temperature2It is dry that (100mg, 1eq) is dissolved in molecular sieve
In the solvent 20mL DCM of dry mistake, the DMAP (1eq) of 12mg is added.After reacting 6h, after TLC detects fully reacting, reaction solution
It is washed with 2mol/L dilute hydrochloric acid, then extracts (20mL × 3) with DCM, merge organic phase, after anhydrous sodium sulfate drying, use vacuum
Rotary Evaporators are rotated to doing, and obtain crude product.Crude product is using ether mashing (3mL × 3), and centrifugation, finally obtaining purity is
97% white solid product, i.e. compound IIIb 138mg, yield 85%.
1H NMR(400MHz,CDCl3): δ 5.85-5.65 (m, 1H), 4.42-4.19 (m, 4H), 3.68 (d, J=
107.7Hz,88H),3.38(s,3H),3.29(s,2H),2.35-2.32(s,4H),1.73(s,2H),1.66(s,4H),1.26
(m, 48H), 0.87 (d, J=6.5Hz, 6H)
MS (ESI): m/z=1625.12 [M+H]+。
The preparation of (1000)-ten six carbon diacylglycerol of 7 compound IIIc, that is, mPEG of embodiment
Compound IIc (147mg, 2eq) and mPEG (1000)-NH are taken at room temperature2It is dry that (100mg, 1eq) is dissolved in molecular sieve
In the solvent 20mL DCM of dry mistake, the DMAP (1eq) of 12mg is added.After reacting 6h, after TLC detects fully reacting, reaction solution
It is washed with 2mol/L dilute hydrochloric acid, then extracts (20mL × 3) with DCM, merge organic phase, after anhydrous sodium sulfate drying, use vacuum
Rotary Evaporators are rotated to doing, and obtain crude product.Crude product is using ether mashing (3mL × 3), and centrifugation, finally obtaining purity is
96% white solid product, i.e. compound IIIc 140mg, yield 85%.
1H NMR(400MHz,CDCl3): δ 5.85-5.8 (m, 1H), 4.42-4.20 (m, 4H), 3.68 (d, J=
107.7Hz,88H),3.38(s,3H),3.29(s,2H),2.35-2.32(s,4H),1.73(s,2H),1.661(s,4H),
1.26 (m, 52H), 0.87 (d, J=6.5Hz, 6H)
MS (ESI): m/z=1653.15 [M+H]+。
The preparation of (1000)-ten seven carbon diacylglycerol of 8 compound IIId, that is, mPEG of embodiment
Compound IId (147mg, 2eq) and mPEG (1000)-NH are taken at room temperature2It is dry that (100mg, 1eq) is dissolved in molecular sieve
In the solvent 20mL DCM of dry mistake, the DMAP (1eq) of 12mg is added.After reacting 6h, after TLC detects fully reacting, reaction solution
It is washed with 2mol/L dilute hydrochloric acid, then extracts (20mL × 3) with DCM, merge organic phase, after anhydrous sodium sulfate drying, use vacuum
Rotary Evaporators are rotated to doing, and obtain crude product.Crude product is using ether mashing (3mL × 3), and centrifugation, finally obtaining purity is
96% white solid product, i.e. compound IIId 137mg, yield 85%.
1H NMR(400MHz,CDCl3): δ 5.85-5.8 (m, 1H), 4.42-4.29 (m, 4H), 3.68 (d, J=
107.7Hz,180H),3.38(s,3H),3.29(s,2H),2.35-2.32(s,4H),1.77(s,2H),1.61(s,4H),
1.26 (m, 56H), 0.87 (d, J=6.5Hz, 6H)
MS (ESI): m/z=1681.18 [M+H]+。
The preparation of (2000)-ten four carbon diacylglycerol of 9 compound IIIe, that is, mPEG of embodiment
Compound IIa (133mg, 2eq) and mPEG (2000)-NH are taken at room temperature2It is dry that (197mg, 1eq) is dissolved in molecular sieve
In the solvent 20mL DCM of dry mistake, the DMAP (1eq) of 12mg is added.After reacting 6h, after TLC detects fully reacting, reaction solution
It is washed with 2mol/L dilute hydrochloric acid, then extracts (20mL × 3) with DCM, merge organic phase, after anhydrous sodium sulfate drying, use vacuum
Rotary Evaporators are rotated to doing, and obtain crude product.Crude product is using ether mashing (3mL × 3), and centrifugation, finally obtaining purity is
97% white solid product, i.e. compound IIIe 218mg, yield 85%.
1H NMR(400MHz,CDCl3): δ 5.45-5.09 (m, 1H), 4.42-4.09 (m, 4H), 3.68 (d, J=
107.7Hz,180H),3.38(s,3H),3.29(s,2H),2.31(s,4H),1.77(s,2H),1.61(s,4H),1.26(m,
44H), 0.87 (d, J=6.5Hz, 6H)
MS (ESI): m/z=2609.69 [M+H]+。
The preparation of 10 compound IIIf, that is, mPEG (2000) of embodiment-pentadecane diacylglycerol
At room temperature by compound IIb (280mg, 2eq) and mPEG (2000)-NH2It is dry that (394mg, 1eq) is dissolved in molecular sieve
In the solvent 20mL DCM of dry mistake, the DMAP (1eq) of 24mg is added.After reacting 6h, after TLC detects fully reacting, reaction solution
Washed with the dilute hydrochloric acid of 2mol/L, then extract (30mL × 3) with DCM, merge organic phase, with anhydrous sodium sulfate it is dry after, with true
Empty Rotary Evaporators are rotated to doing, and obtain crude product.Crude product is using ether mashing (3mL × 3), and centrifugation, obtaining purity is 97%
White solid product, i.e. compound IIIf 415mg, yield 80%.
1H NMR(400MHz,CDCl3): δ 5.45-5.09 (m, 1H), 4.42-4.09 (m, 4H), 3.68 (d, J=
107.7Hz,180H),3.38(s,3H),3.29(s,2H),2.31(s,4H),1.77(s,2H),1.61(s,4H),1.26(m,
48H), 0.87 (d, J=6.5Hz, 6H)
MS (ESI): m/z=2637.72 [M+H]+。
The preparation of (2000)-ten six carbon diacylglycerol of 11 compound IIIg, that is, mPEG of embodiment
Compound IIc (147mg, 2eq) and mPEG (2000)-NH are taken at room temperature2It is dry that (197mg, 1eq) is dissolved in molecular sieve
In the solvent 20mL DCM of dry mistake, the DMAP (1eq) of 12mg is added.After reacting 6h, after TLC detects fully reacting, reaction solution
It is washed with 2mol/L dilute hydrochloric acid, then extracts (20mL × 3) with DCM, merge organic phase, after anhydrous sodium sulfate drying, use vacuum
Rotary Evaporators are rotated to doing, and obtain crude product.Crude product is using ether mashing (3mL × 3), and centrifugation, finally obtaining purity is
96% white solid product, i.e. compound IIIg 223mg, yield 85%.
1H NMR(400MHz,CDCl3): δ 5.45-5.09 (m, 1H), 4.42-4.09 (m, 4H), 3.68 (d, J=
107.7Hz,180H),3.38(s,3H),3.29(s,2H),2.31(s,4H),1.77(s,2H),1.61(s,4H),1.26(m,
52H), 0.87 (d, J=6.5Hz, 6H)
MS (ESI): m/z=2665.75 [M+H]+。
The preparation of (2000)-ten seven carbon diacylglycerol of 12 compound IIIh, that is, mPEG of embodiment
Compound IId (147mg, 2eq) and mPEG (2000)-NH are taken at room temperature2It is dry that (197mg, 1eq) is dissolved in molecular sieve
In the solvent 20mL DCM of dry mistake, the DMAP (1eq) of 12mg is added.After reacting 6h, after TLC detects fully reacting, reaction solution
It is washed with 2mol/L dilute hydrochloric acid, then extracts (20mL × 3) with DCM, merge organic phase, after anhydrous sodium sulfate drying, use vacuum
Rotary Evaporators are rotated to doing, and obtain crude product.Crude product is using ether mashing (3mL × 3), and centrifugation, finally obtaining purity is
96% white solid product, i.e. compound IIIh 225mg, yield 85%.
1H NMR(400MHz,CDCl3): δ 5.45-5.09 (m, 1H), 4.42-4.09 (m, 4H), 3.68 (d, J=
107.7Hz,180H),3.38(s,3H),3.29(s,2H),2.31(s,4H),1.77(s,2H),1.61(s,4H),1.26(m,
56H), 0.87 (d, J=6.5Hz, 6H)
MS (ESI): m/z=2693.78 [M+H]+。
Protection content of the invention is not limited to above embodiments.Without departing from the spirit and scope of the invention, originally
Field technical staff it is conceivable that variation and advantage be all included in the present invention, and with appended claims be protect
Protect range.
Claims (9)
1. a kind of method for synthesizing trainingization diacylglycerol, characterized in that it comprises the following steps:
A. anti-under the conditions of solvent, organic base with activator to the hydroxyl in the compound of nitro phenyl chloroformate activation formula (I)
It answers, forms the compound of reactive intermediate, that is, formula (II)；
B. make the compound and mPEG-NH of the formula (II) with solvent and organic base2Reaction forms carbamate structures, synthesizes
The target compound of formula (III)；
Wherein, n=12~15；N'=22~45.
2. the method according to claim 1, wherein in the step a, the compound of the formula (I), the work
The ratio between agent, mole of the organic base are 1~1.2:1.5~3:2~3.
3. the method according to claim 1, wherein in the step a, the solvent be methylene chloride, chloroform,
Toluene, tetrahydrofuran, dichloroethanes or DMF；The organic base is pyridine, triethylamine or diisopropylethylamine.
4. the method according to claim 1, wherein the reaction temperature is 0~25 DEG C, institute in the step a
Stating the reaction time is 0.5~1.5h.
5. the method according to claim 1, wherein in the step a, after the completion of the priming reaction, also into
One step is washed, is dried, being evaporated, column comprising steps of wash away the organic base in reaction solution with dilute hydrochloric acid, then be extracted with dichloromethane
Chromatography；Eluant, eluent in the column chromatography procedure includes the mixture of ethyl acetate, petroleum ether or above-mentioned solvent.
6. the method for synthesis trainingization diacylglycerol according to claim 1, which is characterized in that in the step b, the formula
(II) compound and the mPEG-NH2, the ratio between the mole of the organic base be 1.5~2:1:1.
7. the method according to claim 1, wherein in the step b, the solvent be methylene chloride, chloroform,
Toluene, tetrahydrofuran, dichloroethanes, N,N-dimethylformamide；The organic base includes pyridine, triethylamine, diisopropyl second
Amine or 4-dimethylaminopyridine.
8. the method according to claim 1, wherein the reaction temperature is 0~25 DEG C, institute in the step b
Stating the reaction time is 5~6 hours.
9. the method according to claim 1, wherein in the step b, after the reaction terminates, also into
One step is washed, dried, be evaporated, closed comprising steps of wash away the organic base in reaction solution with dilute hydrochloric acid, then be extracted with dichloromethane
Suitable solvent mashing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610153716.4A CN107200841B (en) | 2016-03-17 | 2016-03-17 | A kind of synthetic method of trainingization diacylglycerol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610153716.4A CN107200841B (en) | 2016-03-17 | 2016-03-17 | A kind of synthetic method of trainingization diacylglycerol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107200841A CN107200841A (en) | 2017-09-26 |
| CN107200841B true CN107200841B (en) | 2019-02-01 |
Family
ID=59903846
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610153716.4A Expired - Fee Related CN107200841B (en) | 2016-03-17 | 2016-03-17 | A kind of synthetic method of trainingization diacylglycerol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107200841B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005051351A2 (en) * | 2003-11-21 | 2005-06-09 | Alza Corporation | Gene delivery mediated by liposome-dna complex with cleavable peg surface modification |
| CN1915968A (en) * | 1999-10-08 | 2007-02-21 | 阿尔萨公司 | Neutral-cationic lipid for nucleic acid and drug delivery |
| EP2119738B1 (en) * | 2007-02-05 | 2014-04-16 | Nippon Shinyaku Co., Ltd. | Polyethylene glycol derivative |
-
2016
- 2016-03-17 CN CN201610153716.4A patent/CN107200841B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1915968A (en) * | 1999-10-08 | 2007-02-21 | 阿尔萨公司 | Neutral-cationic lipid for nucleic acid and drug delivery |
| WO2005051351A2 (en) * | 2003-11-21 | 2005-06-09 | Alza Corporation | Gene delivery mediated by liposome-dna complex with cleavable peg surface modification |
| EP2119738B1 (en) * | 2007-02-05 | 2014-04-16 | Nippon Shinyaku Co., Ltd. | Polyethylene glycol derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107200841A (en) | 2017-09-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110799492B (en) | Novel carbonyl lipid and lipid nanoparticle formulations for delivery of nucleic acids | |
| KR20010024743A (en) | Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors | |
| CN107903389B (en) | Synthesis and application of E-selectin-targeted polyethylene glycol two-end double-modified antitumor drug | |
| WO1996038464A1 (en) | Antimicrobial sterol conjugates | |
| CN106632574B (en) | A kind of compound, preparation method and the usage | |
| CN105085383B (en) | 5 methyl 2 (1H) Pyridione derivatives and its production and use | |
| WO2023245821A1 (en) | Preparation method for n-acetyl-d-galactosamine trimer precursor | |
| CN108863885A (en) | A kind of Ezetimibe and preparation method thereof of mono methoxy polyethylene glycol modification | |
| CN107200841B (en) | A kind of synthetic method of trainingization diacylglycerol | |
| WO2022017317A1 (en) | Method for large-scale synthesis of tetrodotoxin | |
| CN111471080B (en) | ocotillol type ginsengenin A-ring amino thiazole ring derivative and preparation method thereof | |
| JP2002535248A (en) | Cyclic peptide antifungal agent | |
| CN105801438A (en) | Synthetic method of mirabegron intermediate | |
| CN106146355A (en) | Leonurine and the preparation method of aspirin conjugate | |
| CN113387927B (en) | Nitroimidazole derivative for preparing hypoxia imaging agent and preparation method and application thereof | |
| CN115286674A (en) | Cationic liposome and preparation method thereof | |
| CN106083971A (en) | A kind of preparation method of (E) 3 α hydroxyl 6 ethylidene 7 ketone 5 β cholane 24 acid | |
| CN110551064B (en) | Preparation method of isavuconazole sulfate and intermediate thereof | |
| CN111848554B (en) | Synthetic method of sofosbuvir intermediate impurity | |
| CN115594690B (en) | Metformin biotin MetBio, synthesis method thereof and application thereof in nucleic acid drug delivery | |
| CN105566424A (en) | Method for preparing calcium dibutyryladenosine cyclophosphate | |
| CN109651377A (en) | A kind of compound for the treatment of cancer and application thereof | |
| KR101327797B1 (en) | Glycosylated Tricyclo compounds derivatives | |
| CN109265516A (en) | A kind of hybrid peptide and its preparation method and application | |
| CN103804458B (en) | The preparation of three kinds of matrix materials based on cholesterol and application thereof |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder |
Address after: 200241 No. 500, Dongchuan Road, Shanghai, Minhang District Patentee after: EAST CHINA NORMAL University Address before: 200062 No. 3663, Putuo District, Shanghai, Zhongshan North Road Patentee before: EAST CHINA NORMAL University |
|
| CP02 | Change in the address of a patent holder | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190201 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |