CN105833791B - A kind of surfactant containing adjacent nitro benzyl ester light degradation group and preparation method thereof - Google Patents
A kind of surfactant containing adjacent nitro benzyl ester light degradation group and preparation method thereof Download PDFInfo
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- -1 nitro benzyl ester Chemical group 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000004094 surface-active agent Substances 0.000 title claims abstract description 16
- 230000015556 catabolic process Effects 0.000 title claims abstract description 11
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 11
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims abstract description 79
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 10
- 125000006502 nitrobenzyl group Chemical group 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims abstract 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000003480 eluent Substances 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 11
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical group C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 claims description 10
- 239000000543 intermediate Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 150000001649 bromium compounds Chemical class 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 4
- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- CAERQEXHMWMCCV-UHFFFAOYSA-N 4-(bromomethyl)-3-nitrobenzenesulfonic acid Chemical class BrCC1=C(C=C(C=C1)S(=O)(=O)O)[N+](=O)[O-] CAERQEXHMWMCCV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 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 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 21
- 150000007530 organic bases Chemical class 0.000 abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract 2
- UZGKAASZIMOAMU-UHFFFAOYSA-N 124177-85-1 Chemical compound NP(=O)=O UZGKAASZIMOAMU-UHFFFAOYSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 1
- PURWQTAHOUPNBE-UHFFFAOYSA-N [N+](=O)([O-])BrCC1=CC=CC=C1 Chemical group [N+](=O)([O-])BrCC1=CC=CC=C1 PURWQTAHOUPNBE-UHFFFAOYSA-N 0.000 abstract 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 239000012024 dehydrating agents Substances 0.000 abstract 1
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 238000006073 displacement reaction Methods 0.000 abstract 1
- 229910052731 fluorine Inorganic materials 0.000 abstract 1
- 239000011737 fluorine Substances 0.000 abstract 1
- 230000000269 nucleophilic effect Effects 0.000 abstract 1
- 125000004185 ester group Chemical group 0.000 description 16
- 239000000243 solution Substances 0.000 description 10
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 5
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QMAHVAFURJBOFV-UHFFFAOYSA-N 4-(bromomethyl)-3-nitrobenzoic acid Chemical class OC(=O)C1=CC=C(CBr)C([N+]([O-])=O)=C1 QMAHVAFURJBOFV-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- CBFCDTFDPHXCNY-UHFFFAOYSA-N octyldodecane Natural products CCCCCCCCCCCCCCCCCCCC CBFCDTFDPHXCNY-UHFFFAOYSA-N 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- BWRBVBFLFQKBPT-UHFFFAOYSA-N (2-nitrophenyl)methanol Chemical compound OCC1=CC=CC=C1[N+]([O-])=O BWRBVBFLFQKBPT-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940054066 benzamide antipsychotics Drugs 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 2
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- ZLMJMSJWJFRBEC-OUBTZVSYSA-N potassium-40 Chemical compound [40K] ZLMJMSJWJFRBEC-OUBTZVSYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 0 **(C(c1ccc(CN)c(*)c1)=O)N=C Chemical compound **(C(c1ccc(CN)c(*)c1)=O)N=C 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- RAZLJUXJEOEYAM-UHFFFAOYSA-N 2-[bis[2-(2,6-dioxomorpholin-4-yl)ethyl]azaniumyl]acetate Chemical compound C1C(=O)OC(=O)CN1CCN(CC(=O)O)CCN1CC(=O)OC(=O)C1 RAZLJUXJEOEYAM-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 150000004075 acetic anhydrides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical compound ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000002242 deionisation method Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000004298 light response Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- XGZZJMMAOGFTGG-UHFFFAOYSA-N n,n-dioctylbenzamide Chemical compound CCCCCCCCN(CCCCCCCC)C(=O)C1=CC=CC=C1 XGZZJMMAOGFTGG-UHFFFAOYSA-N 0.000 description 1
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a kind of new light degradation surfactant and its preparation, belongs to surfactant field.Its synthesis has three-step reaction：1. the double acid anhydrides of dehydrating agent pyridine catalytic dehydration generation diethylene triamine pentacetic acid (DTPA) are done by raw acetic acid acid anhydride of diethylene triamine pentacetic acid (DTPA)；2. using adjacent nitro benzyl br-derivatives as raw material chloride after react to obtain the double long-chain phosphoamide adjacent nitro benzyl bromines of intermediate contraposition with secondary amine.3. intermediate double long-chain benzyl bromine obtains the surface active molecules of the also light-operated group of adjacent nitro benzyl ester under catalyst with carboxyl nucleophilic displacement of fluorine in the middle of the double acid anhydrides of diethylene triamine pentacetic acid (DTPA) in a solvent.The present invention is dexterously dehydrated into acid anhydride using diethylene triamine pentacetic acid (DTPA), protects the carboxyl of end four, ester is catalyzed into optionally by middle carboxyl organic base DBU, be prepared for adjacent nitro benzyl ester light degradation surfactant.This method shortens reaction process compared with conventional method, drastically increases efficiency.
Description
Technical field
The present invention relates to a kind of novel light-operated surface active molecules and preparation method thereof, and in particular to using adjacent nitro benzyl ester as
Light degradation group, using the double long-chains of secondary amine as hydrophobic grouping, diethylene triamine pentacetic acid (DTPA) divides for the new surface-active of hydrophilic radical
Son and its new method of synthesis, belong to surfactant field.
Background technology
Environmental response amphiphile, amphiphilic molecule assembly receives much concern because of it in the potential application in terms of medicine controlled release, and light
Response is then external controllable and without specific chemical change in vivo.Medicine is wrapped in carrier, intravenous injection is followed into blood
Ring, external ultraviolet or near infrared light is stimulated, and the controlled release of medicine is realized, so as to significantly reduce drug loss and to human body
Toxic side effect, improve bioavilability.
Adjacent nitro benzyl ester has the special construction of two-photon effect, and ester bond can be broken under near infrared light, reach medicine
Thing controlled release effect, the near-infrared controlled release on adjacent nitro benzyl ester causes researcher to pay close attention in recent years.Wherein, Jiang Jinqiang
Et al. devise block copolymer using o-nitro benzyl alcohol as hydrophobic side, esterification introduces ester group, wraps up dewatering medicament Buddhist nun sieve
Red, 365nm or 700nm light irradiation 25min medicines discharge (Macromolecules 2006,39,4633-4640) completely；
Minhyuck Kang and Bongjin Moon et al. is introduced by bridge of adjacent nitro benzyl ester in the middle of the molecule of design, acyl chlorides and benzyl
Alcohol reaction introduce ester group, 350nm ultraviolet light 2h adjacent nitro benzyl ester systems be broken substantially (Macromolecules 2009,
42,455-458)；Dong builds bright et al. by the affine substitution introducing adjacent nitro benzyl ester group of benzyl bromine, and passes through polycondensation diminution vesica grain
Footpath, improves the stability (Langmuir 2012,28,1733-1737) of dispenser carrier.But traditional adjacent nitro benzyl ester is drawn
Enter method, often by substrate of o-nitro benzyl alcohol by with acid anhydrides, acyl chlorides, active Esterification reaction, introduce required photoresponse ester
Base.There is certain structural limitation in such a method, phenyl ring often only in structure end, when it come to enters in structure to phenyl ring
Between, higher is required to the carboxylic acid reactive of esterification, is restricted.
Diethylene triamine pentacetic acid (DTPA) can be used with gadolinium complexing as nuclear magnetism contrast agent, and surface active molecules are introduced in the present invention
Diethylene triamine pentacetic acid (DTPA) will can be used as functional magnetic resonance contrast agent as hydrophilic radical.Diethylene triamine pentacetic acid (DTPA) has five carboxylics
Base, reaction generally requires a carboxyl, therefore needs remaining four carboxy protective to get up, and obtains more single-minded structure.Tradition
Diethylene triamine pentacetic acid (DTPA) carboxyl it is general introduce tert-butyl group alcohol in building-up process and protected into ester, but building-up process step
Rapid cumbersome, the reaction time is longer, and inefficient and carboxyl selective protection is also a difficult point.Arano etc. is with diethylenetriamine
For raw material, carboxyl is protected by bromo-acetic acid tert-butyl during synthesis diethylene triamine pentacetic acid (DTPA), a terminal carboxyl group is left
(J.Med.Chem.1996,39,3451.).Giordano etc. equally first protects end group amine as initial feed using diethylenetriamine,
It is finally synthesizing the diethylenetriamine derivative (Synthesis 2004,1835.) for leaving middle carboxyl.Davies etc. is with 2,2'-
Dichlorodiethyl amine hydrochlorate is raw material, in protecting two end carboxyls to leave during synthesis diethylene triamine pentacetic acid (DTPA) derivative
Between carboxyl (J.Pept.Sci.2002,8,663.).
The content of the invention
It is a kind of double with benzyl br-derivatives and diethylene triamine pentacetic acid (DTPA) using organic base DBU it is an object of the invention to propose
Acid anhydride is the synthetic method for the surfactant that Material synthesis contains adjacent nitro benzyl ester photosensitive group.This method is inversely wanted to examine, ingenious
The remaining middle carboxyl of utilization diethylene triamine pentacetic acid (DTPA) acid anhydride activated carboxyl, synthesized degradable surfactant.
The present invention provides a kind of surfactant containing adjacent nitro benzyl ester photosensitive group, and general structure I is as follows：
Wherein, m and n are separately selected from 6,8,10,12 or 14.M and n be able to can also be differed with identical；It is preferred that m
=n.
The present invention provides a kind of system of the new light-operated surfactant molecule of light degradation surfactant o p-Nitrobenzyl again
Preparation Method：
By the double acid anhydrides of diethylene triamine pentacetic acid (DTPA) in single-necked flask, add anhydrous solvent and be heated to 60~70 DEG C of dissolvings, it is cold
But room temperature is arrived, the double long-chain bromo derivatives being dissolved in anhydrous solvent are added dropwise；With the catalyst DBU being dissolved in anhydrous solvent, nitrogen
Under gas shielded, 30~80 DEG C of reaction 1h add suitable quantity of water into reaction solution, produce milky white liquid, and centrifugation obtains lower floor's khaki
Solid, column chromatography for separation, eluant, eluent is the mixed liquor of dichloromethane and methanol, obtains the light-operated surface active molecules of adjacent nitro benzyl ester bright
Yellow solid；
Described pair of long-chain bromo derivative structure such as formula II：
Wherein, m and n are separately selected from 6,8,10,12 or 14.M and n be able to can also be differed with identical；It is preferred that m
=n.
The double acid anhydrides of diethylene triamine pentacetic acid (DTPA)：Double long-chain bromo derivatives：Catalyst DBU：Water mol ratio is 1：0.8-1.2：
0.8-1.2：40-60；
The double acid anhydrides of diethylene triamine pentacetic acid (DTPA)：Solvent molar ratio is：1：250-350.
Further, in the above-mentioned technical solutions, it is double long in the double long-chain bromo derivatives being dissolved in anhydrous solvent
Chain bromo derivative is 1 with anhydrous solvent mol ratio:50-60；Catalyst in the catalyst DBU being dissolved in anhydrous solvent
DBU is 1 with anhydrous solvent mol ratio:50-60.
Further, in the above-mentioned technical solutions, the anhydrous solvent is selected from DMSO or DMF.
Further, in the above-mentioned technical solutions, the preparation method of described pair of long-chain bromo derivative intermediate is：
Adjacent nitro benzyl br-derivatives are taken in three-necked flask, is added dropwise after thionyl chloride, 2~5h of back flow reaction and removes excessive two
Chlorine sulfoxide.Appropriate double long-chain secondary amine and appropriate potassium carbonate is added dropwise, 30~60 DEG C of reaction 12h stop reaction, add appropriate deionization
Water, point liquid, organic layer is stayed overnight with anhydrous sodium sulfate drying, and eluant, eluent is the mixed liquor of dichloromethane and methanol, column chromatography for separation,
Obtain benzyl br-derivatives pale yellow oily liquid.
Double long-chain secondary amine structure such as general formula IIIs:
Wherein, m and n are separately selected from 6,8,10,12 or 14.M and n be able to can also be differed with identical；It is preferred that m
=n.
Adjacent nitro benzyl br-derivatives：Thionyl chloride：Double long-chain secondary amine：Potassium carbonate mol ratio is：1：60-80：0.8-1.2：
0.8-1.2。
Further, in the above-mentioned technical solutions, the adjacent nitro benzyl br-derivatives are selected from 4- bromomethyl -3- nitrobenzoyls
Acid or 4- bromomethyl -3- nitrobenzene-sulfonic acids.
Further, in the above-mentioned technical solutions, eluant, eluent used in synthesizing double long-chain bromo derivative intermediates is dichloro
The volume ratio (20~40) of methane and methanol:1 mixed liquor；
Eluant, eluent used in the synthesis light-operated surface active molecules of adjacent nitro benzyl ester is that the volume ratio of dichloromethane and methanol is (10
~20)：1 mixed liquor.
Further, in the above-mentioned technical solutions, the preparation method of the double acid anhydrides (DTPAA) of the diethylene triamine pentacetic acid (DTPA)
For：
Diethylene triamine pentacetic acid (DTPA) is put in single-necked flask, acetic anhydride is sequentially added, pyridine is warming up under nitrogen protection
60~70 DEG C, react 20~24h.Reaction finishes suction filtration, obtains the double acid anhydride white solid powders of diethylene triamine pentacetic acid (DTPA).
The chemical reactive synthesis formula of surface active molecules of the present invention is as follows：
Wherein, m and n are separately selected from 6,8,10,12 or 14.M and n be able to can also be differed with identical；It is preferred that m
=n.
The ingenious part of the synthesis mechanism is to utilize the method for being dehydrated into acid anhydride activated carboxyl by diethylene triamine pentacetic acid (DTPA)
The carboxy protective at two ends, makes centre under organic base DBU (carbon -7- alkene of 1,8- diazabicylo 11) high selectivity catalytic action
A remaining carboxyl reacts with benzyl halogen.The acid anhydrides at two ends can also be subsequently recycled to carry out next step reaction, so both
The reactivity that reaction selectivity improves two end carboxyls again is added, is killed two birds with one stone.
Invention beneficial effect
The present invention has dexterously been catalyzed diethylenetriamine using the characteristic of organic base DBU efficient catalytic nucleophilic substitution reactions
Relatively inactive carboxyl and benzyl br-derivatives reaction generation degradable surfactant, both protect end in the double acid anhydrides of pentaacetic acid
Carboxyl improves reaction selectivity again, kills two birds with one stone.
(1) present invention is dexterously dehydrated into acid anhydride using diethylene triamine pentacetic acid (DTPA) itself, has both served the work of carboxy protective
With again optionally there is provided the carboxyl needed for a reaction.
(2) present invention shortens routine normal-butyl alcohol as raw material, greatly in conjunction using the double acid anhydrides of diethylene triamine pentacetic acid (DTPA)
The complex reaction flow of carboxyl is protected during into diethylene triamine pentacetic acid (DTPA), efficiency is improved.
(3) present invention is using organic base DBU high catalytic reaction activity, and benzyl bromine sets out with carboxylic acid reaction into ester, single-phase anti-
Should there is provided a kind of new esterification response path.
Brief description of the drawings
Fig. 1 is surface active molecules (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- bis- prepared by embodiment 1
The mass spectrogram of octyl group benzamide；
Fig. 2 is surface active molecules (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- bis- prepared by embodiment 1
Octyl group benzamide1H NMR scheme.
Embodiment
The method of the present invention is described further with reference to embodiment, but is not limitation of the invention.
The light degradation surfactant of embodiment 1 (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- dioctyl benzene first
The synthesis of acid amides：
(1) diethylene triamine pentacetic acid (DTPA) acid anhydride is synthesized
3.98g (0.01mol) diethylene triamine pentacetic acid (DTPA)s are weighed with 100mL single-necked flasks, sequentially adding 4mL acetic anhydrides
With 5mL pyridines, 65 DEG C are warming up under nitrogen protection, 24h is reacted.Reaction finishes suction filtration, obtains white solid powder.Fusing point：178
℃-184℃
(2) N, N- dioctyl benzamide bromo derivative intermediates are synthesized
1g (0.004mol) 4- bromomethyl -3- nitrobenzoic acids are taken in 100mL three-necked flasks, under magnetic agitation, are added dropwise
10mL thionyl chlorides, back flow reaction 3h, reaction is finished, and revolving removes excessive thionyl chloride.0.96g is added dropwise into three-necked flask
(0.004mol) two n-octyl amine, completion of dropping adds 0.5g (0.004mol) potassium carbonate, and 40 DEG C of reaction 12h stop reaction, plus
Enter appropriate amount of deionized water, point liquid, organic layer anhydrous sodium sulfate drying, chromatography post separation eluant, eluent is dichloromethane and methanol
Volume ratio is 40:1 mixed liquor, obtains pale yellow oily liquid.Yield 76.0%.
(3) (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- dioctyl benzamide is synthesized
Take the double acid anhydrides of 0.22g (0.0006mol) diethylene triamine pentacetic acid (DTPA) in 100mL single-necked flasks, add 10mL anhydrous
DMF is heated to 60 DEG C of dissolvings, is cooled to room temperature, is first added dropwise and is dissolved in bromination product in DMF, then 0.1g is added dropwise and is dissolved in DMF
DBU, under nitrogen protection, 50 DEG C of reaction 1h add suitable quantity of water into reaction solution, produce milky white liquid, and centrifugation obtains lower floor's colour of loess
Color solid, column chromatography for separation, eluant, eluent is dichloromethane and methanol volume ratio is 10：1 mixture, obtains bright yellow solid (4-
Diethylene triamine pentacetic acid (DTPA) ester group) -3- nitros-N, N- dioctyl benzamide.Yield 18.2%.
Fig. 1 is surface active molecules (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- bis- prepared by embodiment 1
The mass spectrogram of octyl group benzamide；
MS:m/z[M-H]-794.50,[M/2-H]-396.88,[M+H]+796.45,[M+Na]+818.45
Fig. 2 is surface active molecules (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- bis- prepared by embodiment 1
Octyl group benzamide1H NMR scheme.
1H NMR(400MHz,CD2Cl2,CD3OD):δin ppm 0.90-0.84(m,6H,2×CH3-CH2-)；1.37-
1.13(m,24H,2×-(CH2)6-CH3)；2.21-1.53(m,8H,2×-N-CH2-CH2-N-)；3.33(s,14H,5×-N-
CH2-COO-,2×-CO-N-CH2-CH2-)；5.50-5.54(s,2H,-O-CH2-C6H6-)；7.68(d,1H,-C6H6-)；7.95
(d,1H,-C6H6-)；8.09(s,1H,-C6H6-)
The light degradation surfactant of embodiment 2 (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- didecyl benzene first
The synthesis of acid amides：
(1) diethylene triamine pentacetic acid (DTPA) acid anhydride is synthesized
Be the same as Example 1
(2) N, N- didecyl yl-benzamide bromo derivative intermediates are synthesized
1g (0.004mol) 4- bromomethyl -3- nitrobenzoic acids are taken with 100mL three-necked flasks, under magnetic agitation, being added dropwise
10mL thionyl chlorides, back flow reaction 4h, reaction is finished, and revolving removes excessive thionyl chloride.1.19g is added dropwise into three-necked flask
(0.004mol) two n-Decylamine, completion of dropping adds 0.5g (0.004mol) potassium carbonate, and 50 DEG C of reaction 15h stop reaction, plus
Enter appropriate amount of deionized water, point liquid, organic layer anhydrous sodium sulfate drying, chromatography post separation eluant, eluent is dichloromethane and methanol
Volume ratio is 40:1 mixed liquor, obtains pale yellow oily liquid.Yield 62.1%.
(3) (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- didecyl yl-benzamide is synthesized
Take the double acid anhydrides of 0.22g (0.0006mol) diethylene triamine pentacetic acid (DTPA) in 100mL single-necked flasks, add 10mL anhydrous
DMF is heated to 70 DEG C of dissolvings, is cooled to room temperature, is first added dropwise and is dissolved in bromo derivative in DMF, then 0.1g is added dropwise and is dissolved in DMF
DBU, under nitrogen protection, 60 DEG C of reaction 3h add suitable quantity of water into reaction solution, produce milky white liquid, centrifuge, obtain subsoil
Yellow solid, chromatography post separation eluant, eluent is that the volume ratio of dichloromethane and methanol is 10:1 mixed liquor, crosses post separation, obtains bright
Yellow solid (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- didecyl yl-benzamide.Yield 18.6%.
The lauryl amines of the light degradation surface active molecules of embodiment 3 (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N- bis-
The synthesis of yl-benzamide：
(1) diethylene triamine pentacetic acid (DTPA) acid anhydride is synthesized
Be the same as Example 1
(2) synthetic bromide is for derivatives intermediates
1g (0.004mol) 4- bromomethyl -3- nitrobenzoic acids are taken with 100mL three-necked flasks, under magnetic agitation, being added dropwise
10mL thionyl chlorides, back flow reaction 3h, reaction is finished, and revolving removes excessive thionyl chloride.1.47g is added dropwise into three-necked flask
(0.004mol) double lauryl amines, completion of dropping adds 0.5g (0.004mol) potassium carbonate, and 40 DEG C of reaction 12h stop reaction, plus
Enter appropriate amount of deionized water, point liquid, organic layer anhydrous sodium sulfate drying, chromatography post separation eluant, eluent is dichloromethane and methanol
Volume ratio is 40:1 mixed liquor, obtains pale yellow oily liquid.Yield 46.5%.
(3) the double lauryl amine yl-benzamides of synthesis (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N-
Take the double acid anhydrides of 0.22g (0.0006mol) diethylene triamine pentacetic acid (DTPA) in 100mL single-necked flasks, add 10mL anhydrous
DMF is heated to 70 DEG C of dissolvings, is cooled to room temperature, and the bromination product being dissolved in DMF is added dropwise.Completion of dropping, then 0.1g is added dropwise is dissolved in
DBU in DMF, under nitrogen protection, 50 DEG C of reaction 1.5h add suitable quantity of water into reaction solution, produce milky white liquid, centrifuge,
Subsoil yellow solid, chromatography post separation eluant, eluent is that the volume ratio of dichloromethane and methanol is 10:1 mixed liquor, crosses post
Separation, obtains the double lauryl amine yl-benzamides of bright yellow solid (4- diethylene triamine pentacetic acid (DTPA)s ester group) -3- nitros-N, N-.Yield
18.4%.
Claims (10)
1. a kind of surfactant containing adjacent nitro benzyl ester light degradation group, structure such as formula I,
Wherein, m and n are separately selected from 6,8,10,12 or 14.
2. a kind of preparation method of the surfactant containing adjacent nitro benzyl ester light degradation group, it is characterised in that：
Anhydrous solvent is added in the double acid anhydrides of diethylene triamine pentacetic acid (DTPA) and is heated to 60~70 DEG C of dissolvings, room temperature is cooled to, is added dropwise
It is dissolved in double long-chain bromo derivatives in anhydrous solvent；The catalyst DBU being dissolved in anhydrous solvent is added dropwise, under nitrogen protection, 30
~80 DEG C of reaction 1-2h, water is added into reaction solution, produces milky white liquid, and centrifugation obtains subsoil yellow solid, column chromatography point
From eluant, eluent is the mixed liquor of dichloromethane and methanol, obtains the light-operated surface active molecules bright yellow solid of adjacent nitro benzyl ester；
Described pair of long-chain bromo derivative structure such as formula II：
Wherein, m and n are separately selected from 6,8,10,12 or 14.
3. preparation method according to claim 2, it is characterised in that：The double acid anhydrides of diethylene triamine pentacetic acid (DTPA)：Double long-chain bromos
Derivative：Catalyst DBU：Water mol ratio is 1：0.8-1.2：0.8-1.2：40-60.
4. preparation method according to claim 2, it is characterised in that：The double acid anhydrides of diethylene triamine pentacetic acid (DTPA)：Anhydrous solvent rubs
You are than being 1：250-350.
5. preparation method according to claim 2, it is characterised in that：The anhydrous solvent is selected from DMSO or DMF.
6. preparation method according to claim 2, it is characterised in that the preparation of described pair of long-chain bromo derivative intermediate
Method is：
It is added dropwise into adjacent nitro benzyl br-derivatives after thionyl chloride, 2~5h of back flow reaction and removes excessive thionyl chloride；It is added dropwise double long
Chain secondary amine and potassium carbonate, 30~60 DEG C of reaction 10-14h stop reaction, add deionized water, point liquid, organic layer anhydrous slufuric acid
Sodium is dried overnight, and eluant, eluent is the mixed liquor of dichloromethane and methanol, and column chromatography for separation obtains benzyl br-derivatives pale yellow oily liquid
Body；
Double long-chain secondary amine structure such as general formula IIIs:
Wherein, m and n are separately selected from 6,8,10,12 or 14.
7. according to the preparation method described in claim 6, it is characterised in that：Adjacent nitro benzyl br-derivatives：Thionyl chloride：Double long-chains
Secondary amine：Potassium carbonate mol ratio is 1：60-80：0.8-1.2：0.8-1.2.
8. preparation method according to claim 6, it is characterised in that：The adjacent nitro benzyl br-derivatives are selected from 4- bromine first
Base -3- nitrobenzoic acids or 4- bromomethyl -3- nitrobenzene-sulfonic acids.
9. preparation method according to claim 6, it is characterised in that：
Eluant, eluent used in the double long-chain bromo derivative intermediates of synthesis is the volume ratio (20~40) of dichloromethane and methanol:1
Mixed liquor.
10. preparation method according to claim 2, it is characterised in that：Synthesize the light-operated surface active molecules of adjacent nitro benzyl ester
Eluant, eluent used is that the volume ratio of dichloromethane and methanol is (10~20)：1 mixed liquor.
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