CN102167802A - Method for preparing poly alpha-hydroxy acid by catalyzing N-heterocyclic carbene - Google Patents
Method for preparing poly alpha-hydroxy acid by catalyzing N-heterocyclic carbene Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 229940061720 alpha hydroxy acid Drugs 0.000 title claims abstract description 20
- 150000001280 alpha hydroxy acids Chemical class 0.000 title claims abstract description 20
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- -1 alcohol compound Chemical class 0.000 claims abstract description 13
- 239000003999 initiator Substances 0.000 claims abstract description 10
- 230000035484 reaction time Effects 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000001569 carbon dioxide Substances 0.000 claims description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000003851 azoles Chemical class 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- 229960004217 benzyl alcohol Drugs 0.000 claims description 3
- 229940067107 phenylethyl alcohol Drugs 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 abstract description 16
- 201000007909 oculocutaneous albinism Diseases 0.000 abstract description 14
- 239000003054 catalyst Substances 0.000 abstract description 5
- 229920000642 polymer Polymers 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 150000008065 acid anhydrides Chemical class 0.000 abstract 1
- 238000005260 corrosion Methods 0.000 abstract 1
- 230000007797 corrosion Effects 0.000 abstract 1
- 229910021645 metal ion Inorganic materials 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000004062 sedimentation Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000009466 transformation Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229920000747 poly(lactic acid) Polymers 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000004310 lactic acid Substances 0.000 description 4
- 235000014655 lactic acid Nutrition 0.000 description 4
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical group CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 229920000954 Polyglycolide Polymers 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000004633 polyglycolic acid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YHWCPXVTRSHPNY-UHFFFAOYSA-N butan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] YHWCPXVTRSHPNY-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009313 farming Methods 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
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- Polyesters Or Polycarbonates (AREA)
Abstract
The invention discloses a method for preparing poly alpha-hydroxy acid by catalyzing N-heterocyclic carbene. The method comprises the steps of taking N-heterocyclic carbene as a catalyst, adding an alcohol compound as an initiator, and carrying out ring-opening polymerization on various protected and unprotected alpha-hydroxy acid-O-carboxyl internal acid anhydrides (OCAs), wherein the reaction temperature is-50-250 ℃, the molar ratio of the N-heterocyclic carbene to the initiator to the OCA is 1: 0.2-5: 2-10000, and the reaction time is 3 seconds-120 hours. The method has the advantages of high catalyst reaction activity, high reaction speed, relatively mild reaction conditions, no introduction of metal ions, no equipment corrosion, simple product post-treatment, narrow molecular weight distribution of the obtained polymer and controllable molecular weight.
Description
Technical field
The present invention relates to a kind of macromolecular material, be specifically related to a kind of method of the N-of use heterocycle carbine catalyzed preparation of poly alpha hydroxy acid.
Background technology
Poly-alpha hydroxy acid is the polyester material that a class has good biodegradability properties energy and physiologically acceptable performance, in every field such as worker, farming, doctors important use is arranged.
Using maximum poly-alpha hydroxy acid at present is polyglycolic acid (PGA) and poly(lactic acid) (PLA).They are not only biodegradable polymkeric substance under the organism environment, and have excellent biological compatibility, can biological assimilate.PGA and PLA can be by the lactide ring-opening polymerizations of oxyacetic acid and lactic acid, and perhaps direct condensation prepares.The method reaction conditions of direct condensation requires high, and the polymericular weight of gained is little, poor performance, the therefore general method that all adopts ring-opening polymerization.
Poly-alpha hydroxy acid particularly has a wide range of applications in the drug targeting administration in pharmaceutically application.But when further concrete the application, polymer architecture needs tailor-make as requested, and its physicochemical property not only will satisfy it can pass various physiologic barriers, and wants accurately to carry medicine to the administration target spot and discharge.Because side chain has the lactide of function functional group and is difficult to preparation, the limitation of reaction raw materials has limited poly-alpha hydroxy acid and itself has had more function, the performance of resultant multipolymer when also having limited with other monomer formation multipolymer.
Alpha hydroxy acid-O-carboxyl inner-acid anhydride (OCAs) is a kind of five member ring heterocyclic compound, can be used as the monomer of the poly-alpha hydroxy acid of ring-opening polymerization preparation, because of it is easy to prepare the ring-opening polymerization raw material of functional side chain functional group, and speed of reaction is faster than lactide, thereby is subjected to people's attention.OCA can make by the alpha hydroxy acid phosgenation (Journal of the Chemical Society, 1951,1357-1359).
H.R.Kricheldorg and J.M.Jonte (Polymer Bulletin, 1983,92,276-281) prepared the polymkeric substance of lactic acid by lactic acid OCA ring-opening polymerization, used catalyzer is a kind of in pyridine, triethylamine, potassium tert.-butoxide and the tetrabutyl titanate.But the polymkeric substance of gained is oligopolymer, and molecular weight is all less than 3000.Smith.J and Tighe.J (Makromol.Chem.1981,182,313) have caused the ring-opening polymerization of amygdalic acid OCA with pyridine and substituted pyridines, have obtained similar result.
(Journal of the American Chemical Society such as Dider Bourissou, 2006,128,16442) reported that with 4-Dimethylamino pyridine (DMAP) be catalyzer, catalysis lactic acid OCA prepares poly(lactic acid), has controlled the molecular weight and the dispersity of polymkeric substance preferably.They (Chemical Communications, 2008,1786) have reported that again the OCA ring-opening polymerization by the corresponding alcohol acid of L-L-glutamic acid prepares the phase emergencing copolymer, still uses DMAP as catalyzer subsequently.In the experimentation side chain carboxyl group is protected; finally having obtained side chain is the polymkeric substance of function functional group carboxyl; and delivered the relevant PCT patent (WO2007113304A1) of this type of catalyst OCA ring-opening polymerization, for the research of this type of functional polymer is laid a good foundation.
Cabbeen is the efficient organic catalyst of a class, enjoys the chemist to pay close attention in recent years.G. W.Nyce etc. (Journal of theAmerican Chemical Society, 2003,125,3046) utilizes nucleophilic N-heterocycle carbine (NHC) to obtain poly(lactic acid) as active catalyst ring-opening polymerization rac-Lactide.But N-heterocycle carbine and active, very responsive with water to air, the aerial life-span only is several seconds, directly uses its catalyzed polymerization, is difficult to operation.
In order to overcome this drawback, chemists have carried out more research to the storage form of N-heterocycle carbine.(Journal of the American Chemical Society such as Eric F.Connor; 2002; 124; 914) with azoles salt as N-heterocycle carbine precursor; at first under the effect of highly basic potassium tert.-butoxide etc., generate corresponding N-heterocycle carbine, under protection of inert gas, filter then and obtain the N-heterocycle carbine.(Chemical Communications, 2004,112) such as Hung A.Duong are also found: N-heterocycle carbine and CO
2Reaction can generate air and the stable Cabbeen carbon dioxide adduct of water.At a certain temperature, the Cabbeen carbon dioxide adduct can directly be sloughed CO in reaction solvent
2, discharge activated Cabbeen.Li Zhenjiangs etc. provide the Cabbeen carbon dioxide adduct to be used for the technical scheme of ring-opening polymerization in patent (CN101665567).
Compare with DMAP catalysis OCA ring-opening polymerization, carbene catalyzed this type of reaction not only can obtain molecular weight and controllable structure, the poly-alpha hydroxy acid of narrow molecular weight distribution, and also catalytic efficient is higher.Present Cabbeen also of no use, carbene precursor more of no use is as the report of catalyzer ring-opening polymerization OCA.
Summary of the invention
The invention provides a kind of method with N-heterocycle carbine catalyzed preparation of poly alpha hydroxy acid, this method has that reaction is controlled, and speed of response is fast, and reaction conditions is gentle relatively, no metal residual, advantage such as it is narrow to obtain molecular weight distribution, and molecular weight is controlled.
The invention provides a kind of method for preparing alpha hydroxy acid, it is characterized in that with the N-heterocycle carbine, add alcohol compound as initiator, the various alpha hydroxy acid-O-carboxyl inner-acid anhydrides that contain different functional side chain groups of ring-opening polymerization as catalyzer.
In the above-mentioned method for preparing peptide, described N-heterocycle carbine structural formula (I), formula (II), formula (III) or formula (IV)
R wherein
1And R
2Be selected from hydrogen, have 1～10 carbon atom alkyl, have 1～10 carbon atom and by the alkyl of one or more replacements in halogen atom, hydroxyl, phenyl and the cyano group, cycloalkyl, phenyl or by the identical or different group in the phenyl of one or more replacements in halogen atom, hydroxyl, alkyl and the cyano group with 3～6 carbon atoms; R
3And R
4Be selected from hydrogen, halogen atom, cyano group, hydroxyl, have 1～4 carbon atom alkyl, have 1～4 carbon atom and by the alkyl of one or more replacements in halogen atom, hydroxyl, phenyl and the cyano group, phenyl or by the identical or different group in the phenyl of one or more replacements in halogen atom, hydroxyl, alkyl and the cyano group.
The concrete technical scheme of the present invention comprises:
(1) preparation of N-heterocycle carbine: (a) under nitrogen, argon shield, N-heterocycle carbine carbon dioxide adduct at 50 ℃～250 ℃, reacted 3 seconds～20 hours in organic solvent, sloughed CO
2The back generates.(b) under nitrogen, argon shield; with one or more 1: 0.001 in molar ratio～5 are blended in the organic solvent in N-heteroaryl salt and potassium tert.-butoxide, sodium tert-butoxide, lithium hydride, the potassium hydride KH; under 0 ℃～100 ℃, reacted 1 minute～20 hours, obtain after the filtration.
(2) in the above-mentioned solution that contains the N-heterocycle carbine, add alpha hydroxy acid-O-carboxyl inner-acid anhydride and initiator, obtain product after treatment.
The structural formula of N-heterocycle carbine carbon dioxide adduct is formula V, formula (VI), formula (VII) or formula (VIII) among the above-mentioned N-heterocycle carbine preparation method
R wherein
1, R
2, R
3, R
4With substituent R described in the N-heterocycle carbine structural formula
1, R
2, R
3, R
4Identical.
The structural formula of azoles salt is formula (IX), formula (X), formula (XI) or formula (XII) among the above-mentioned N-heterocycle carbine preparation method
R wherein
1, R
2, R
3, R
4With substituent R described in the N-heterocycle carbine structural formula
1, R
2, R
3, R
4Identical.X
-Be Cl
-, Br
-, I
-, BF
4 -, PF
6 -, CF
3SO
3 -, NO
3 -, SO
4 2-, CH
3COO
-, CF
3COO
-, CH
3C
6H
5COO
-, SCN
-In any one.
Organic solvent is dioxane, methylene dichloride, trichloromethane, tetrahydrofuran (THF), N,N-dimethylacetamide, N among the above-mentioned N-heterocycle carbine preparation method, dinethylformamide, toluene, dimethylbenzene, methyl-sulphoxide.
In the method for the poly-alpha hydroxy acid of above-mentioned preparation, specifically comprise N-heterocycle carbine, initiator and OCA 1: 0.2 in molar ratio～5: 2～10000, be preferably 1: 0.5～2: 10～200; Temperature of reaction is-50 ℃～250 ℃, is preferably 0 ℃～150 ℃; Reaction times is 3 seconds～120 hours, is preferably 0.2～24 hour.
In the method for the poly-alpha hydroxy acid of above-mentioned preparation, being reflected in the rare gas element in the described method carried out, nitrogen for example, argon gas; Described initiator is an alcohol compound, for example phenylcarbinol, phenylethyl alcohol, propyl carbinol, the trimethyl carbinol, n-propyl alcohol, Virahol, neopentyl alcohol, polyoxyethylene glycol; Can add entry, formic acid, acetate, CS during termination reaction
2Reaction product is at the solvent that settles out, and for example methyl alcohol, ethanol settle out in the ether and carries out purifying.
In the method for the poly-alpha hydroxy acid of above-mentioned preparation, described method can be by successively adding two or more OCA monomer, through the poly-alpha hydroxy acid segmented copolymer of ring-opening polymerization preparation; Also can adopt one pot of feeding method, by two or more OCA monomer, through the poly-alpha hydroxy acid random copolymers of ring-opening polymerization preparation.
The distinguishing feature of method of the present invention is to select for use the N-heterocycle carbine as catalyzer.In polymerization system, do not bring any pollutent into, the method for the poly-alpha hydroxy acid of a kind of efficient, eco-friendly preparation.
Embodiment
Can further specify the present invention by the following example, embodiment is unrestricted of the present invention for explanation.The N-heterocycle carbine carbonic acid gas front body structure that relates in the embodiment of the invention sees Table 1.
Table 1: all Cabbeen adducts numbering and structure table look-ups among the embodiment
Below the catalyzer counter structure of each embodiment see Table 1.
Embodiment 1:
A (31mg, 200 μ mol) is dissolved in the dioxane of 20mL, under the Ar protection, is heated to 100 ℃ and kept 30 minutes; take out being cooled to room temperature, add phenylcarbinol (21.6mg, 200 μ mol), L-phenyllactic acid-O-carboxyl inner-acid anhydride (0.768g then; 4mmol), 0 ℃ was reacted 5 hours down, adds the formic acid termination reaction; reaction solution is poured in the methyl alcohol; sedimentation and filtration also is dried to constant weight, obtains white solid 0.533g, and transformation efficiency is 90%; number-average molecular weight is 2580, and dispersity PDI is 1.18.
Embodiment 2:
B (34.8mg, 100 μ mol) is dissolved in the toluene of 10mL N
2Be heated to 80 ℃ under the protection and kept 1 hour, take out being cooled to room temperature, add phenylethyl alcohol (18.3mg then; 150 μ mol), and L-amygdalic acid-O-carboxyl inner-acid anhydride (1.78g, 10mmol); 100 ℃ were reacted 2 hours; add the entry termination reaction, reaction solution is poured in the ether, sedimentation and filtration also is dried to constant weight; obtain white solid 1.14g; transformation efficiency is 85%, and number-average molecular weight is 7600, and dispersity PDI is 1.29.
Embodiment 3:
D (17.05mg, 50 μ mol) is dissolved in the 10mL tetrahydrofuran (THF), is heated to 150 ℃ under the Ar protection and kept 45 minutes down, take out being cooled to room temperature, add propyl carbinol (5.55mg, 75 μ mol) then, N
ε-carbobenzoxy-(Cbz)-L-Methionin-O-carboxyl inner-acid anhydride (0.765g, 2.5mmol), 50 ℃ were reacted 50 minutes down, add the acetate termination reaction, reaction solution is poured in the ethanol, sedimentation and filtration also is dried to constant weight, obtain white solid 0.564g, transformation efficiency is 86.1%, and number-average molecular weight is 7419, and dispersity PDI is 1.12.
Embodiment 4:
E (11.15mg, 50 μ mol) is dissolved in the 20mL dioxane N
2Being heated to 150 ℃ under the protection kept 50 minutes down.Take out being cooled to room temperature, neopentyl alcohol (8.8mg, 100 μ mol), L-lactic acid-O-carboxyl inner-acid anhydride (2.32g, 20mmol), 25 ℃ were reacted 4 hours down, add the acetate termination reaction, reaction solution is poured in the methyl alcohol, sedimentation and filtration obtains white solid 1.211g to constant weight, and transformation efficiency is 83.6%, number-average molecular weight is 12110, and dispersity PDI is 1.13.
Embodiment 5:
G (5.4mg, 20 μ mol) is dissolved in the 15mL toluene, adds sodium tert-butoxide (4.8mg, 50 μ mol) N
2Protect following 80 ℃ of reactions 30 minutes, filter and obtain Cabbeen solution.Take out being cooled to room temperature, add Virahol (2.4mg, 40 μ mol) then, γ-benzyl-L-L-glutamic acid-O-carboxyl inner-acid anhydride (1.052g, 4mmol), 60 ℃ were reacted 3 hours down, add the water termination reaction, reaction solution is poured in the methyl alcohol, sedimentation and filtration also is dried to constant weight, obtains white solid 0.700g, and transformation efficiency is 80%, number-average molecular weight is 11750, and dispersity PDI is 1.06.
Embodiment 6:
H (7.59mg, 30 μ mol) is dissolved in the 10mL tetrahydrofuran (THF), adds sodium tert-butoxide (14.4mg, 150 μ mol) N again
2Protect following 80 ℃ of reactions 5 minutes, filter and obtain Cabbeen solution.Take out being cooled to room temperature, add neopentyl alcohol (2.64mg, 30 μ mol) then, L-lactic acid-O-carboxyl inner-acid anhydride (0.1044g, 0.9mmol), 80 ℃ were reacted 30 minutes down, add the formic acid termination reaction, reaction solution is poured in the ether, sedimentation and filtration also is dried to constant weight, obtains white solid 0.061g, and transformation efficiency is 88.3%, number-average molecular weight is 1985, and dispersity PDI is 1.12.
Claims (8)
1. method with N-heterocycle carbine catalyzed preparation of poly alpha hydroxy acid; the steps include: in the organic solvent that contains the N-heterocycle carbine, to add under the protection of inert gas initiator and at least a alpha hydroxy acid-O-carboxyl inner-acid anhydride (OCA); described initiator is an alcohol compound; N-heterocycle carbine, initiator and OCA mol ratio are 1: 0.2～10: 2～10000; temperature of reaction is-50 ℃～250 ℃, and the reaction times is 3 seconds～120 hours.
2. method according to claim 1 is characterized in that: described N-heterocycle carbine is structural formula (I), formula (II), formula (III) or formula (N)
R wherein
1And R
2Be selected from hydrogen, have 1～10 carbon atom alkyl, have 1～10 carbon atom and by the alkyl of one or more replacements in halogen atom, hydroxyl, phenyl and the cyano group, cycloalkyl, phenyl or by the identical or different group in the phenyl of one or more replacements in halogen atom, hydroxyl, alkyl and the cyano group with 3～6 carbon atoms; R
3And R
4Be selected from hydrogen, halogen atom, cyano group, hydroxyl, have 1～4 carbon atom alkyl, have 1～4 carbon atom and by the alkyl of one or more replacements in halogen atom, hydroxyl, phenyl and the cyano group, phenyl or by the identical or different group in the phenyl of one or more replacements in halogen atom, hydroxyl, alkyl and the cyano group.
3. method according to claim 1 is characterized in that: described N-heterocycle carbine is by under nitrogen, argon shield, and N-heterocycle carbine carbon dioxide adduct under 50 ℃～250 ℃, reacted 3 seconds～20 hours in organic solvent, sloughed CO
2The back generates the N-heterocycle carbine or under nitrogen, argon shield; with one or more 1: 0.001 in molar ratio～5 are blended in the organic solvent in azoles salt and potassium tert.-butoxide, sodium tert-butoxide, lithium hydride, the potassium hydride KH; under 0 ℃～100 ℃, to react 1 minute～20 hours, filtration obtains.
4. method according to claim 3 is characterized in that: the structure formula V of described N-heterocycle carbine carbon dioxide adduct, formula (VI), formula (VII) or formula (VIII)
R wherein
1, R
2, R
3, R
4With substituent R described in the claim 2
1, R
2, R
3, R
4Identical.
5. method according to claim 3 is characterized in that: described azoles salt structural formula is formula (IX), formula (X), formula (XI) or formula (XII)
R wherein
1, R
2, R
3, R
4With substituent R described in the claim 2
1, R
2, R
3, R
4Identical.X
-Be Cl
-, Br
-, I
-, BF
4 -, PF
6 -, CF
3SO
3 -, NO
3 -, SO
4 2-, CH
3COO
-, CF
3COO
-, CH
3C
6H
5COO
-, SCN
-In any one.
6. according to claim 1 or 3 described methods, it is characterized in that: described organic solvent is dioxane, methylene dichloride, trichloromethane, tetrahydrofuran (THF), N, N-N,N-DIMETHYLACETAMIDE, N, a kind of or its mixture in dinethylformamide, toluene, dimethylbenzene or the methyl-sulphoxide.
7. method according to claim 1 is characterized in that: rare gas element is argon gas or nitrogen in the described method.
8. method according to claim 1 is characterized in that: described initiator alcohol compound is in phenylcarbinol, phenylethyl alcohol, propyl carbinol, the trimethyl carbinol, n-propyl alcohol, Virahol, neopentyl alcohol, the polyoxyethylene glycol any one.
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| CN101544684A (en) * | 2009-05-06 | 2009-09-30 | 南京工业大学 | Method for preparing peptide by catalyzing N-heterocyclic carbene |
| CN101665565A (en) * | 2008-09-01 | 2010-03-10 | 南京工业大学 | Method for preparing polylactic acid by catalysis of carbene derivative |
| CN101665567A (en) * | 2008-09-01 | 2010-03-10 | 南京工业大学 | Method for controllable ring-opening polymerization of cyclic compound catalyzed by carbene derivative |
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| US20090143551A1 (en) * | 2007-11-15 | 2009-06-04 | Zengquan Qin | Nickel-based catalysts for preparing high cis 1,4-polydienes |
| CN101665565A (en) * | 2008-09-01 | 2010-03-10 | 南京工业大学 | Method for preparing polylactic acid by catalysis of carbene derivative |
| CN101665567A (en) * | 2008-09-01 | 2010-03-10 | 南京工业大学 | Method for controllable ring-opening polymerization of cyclic compound catalyzed by carbene derivative |
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