CN102964603B - Method for synthesizing dendritic compound trifluoroacetate with cage type octa (gamma-aminopropyl) silsesquioxane as core - Google Patents
Method for synthesizing dendritic compound trifluoroacetate with cage type octa (gamma-aminopropyl) silsesquioxane as core Download PDFInfo
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- CN102964603B CN102964603B CN201210420950.0A CN201210420950A CN102964603B CN 102964603 B CN102964603 B CN 102964603B CN 201210420950 A CN201210420950 A CN 201210420950A CN 102964603 B CN102964603 B CN 102964603B
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Abstract
The invention discloses a method for synthesizing a dendritic compound trifluoroacetate with cage type octa (gamma-aminopropyl) silsesquioxane as a core. The method comprises the steps of: dissolving OAS hydrochloride and DIPEA in DMF, dropwise adding DMF N, N '-bis-(tert-butyloxycarbonyl)-L-lysine N-saccinimidyl or N, N'-bis-(tert-butyloxycarbonyl)-L-lysine pentaflurophenyl soluble in DMF, and reacting for 10-14h; adding acetonitrile of -2-2 DEG C, filtering and drying for 20-24 h to obtain t-butyloxycarboryl protected G1 (OL); adding G1 (OL) to trifluoroacetic acid at -2-2 DEG C, and reacting for 3-5h; adding the reaction mixture into diethyl ether of 2-5 DEG C, mixing, standing, filtering and collecting precipitate to obtain G1 (OL) trifluoroacetate; and adjusting reactant proportion, and repeating the above process to obtain the G4 (OL) trifluoroacetate. The invention has advantages of little pollution, short reaction time, simple post-treatment and high yield.
Description
Technical field
The present invention relates to a kind of synthetic method taking poly-(γ-aminopropyl) silicious sesquioxane of cage modle eight as the dendrimer trifluoroacetate (G4 (OL) trifluoroacetate) of core.
Background technology
The organic molecule with dendritic structure is called dendrimer.Dendrimer is generally by being positioned at the core of point subcenter and by the outward extending monomer composition of core.According to the number of plies of monomer repeating can form a generation, two generations until n for dendrimer.As shown in Figure 1, the outer monomer that is with three layers of repetition of the core of this dendrimer (G0), is therefore The Trees of Three Generations dendrimer (being called for short G3).
Dendrimer has extensive use, can make the carrier of catalyzer, medicine or medical science contrast medium etc.Common dendrimer has porphyrin dendrimer, aryl oxide class dendrimer, polyamide-amide class dendrimer (PAMAM), ferrocenyl dendrimer etc.Poly-(γ-aminopropyl) silicious sesquioxane hydrochloride of cage modle eight (being called for short OAS) is a kind of compound with cube structure.The people such as Kaneshiro are taking it as core, taking 1B as monomer, structure four generation dendrimer (being called for short G4 (OL)) trifluoroacetates are as shown in Figure 2 synthesized, this compound trifluoroacetate is medically having broad application prospects, as gene (plasmid DNA) or medicine are transported in cancer cells with treatment cancer (Todd L.Kaneshiro, Xuli Wang, and Zheng-Rong Lu, Synthesis, Characterization, and Gene Delivery of Poly-L-lysine Octa (3-aminopropyl) silsesquioxaneDendrimers:Nanoglobular Drug Carriers with Precisely Defined Molecular Architectures, VOL.4, NO.5, 759-768MOLECULAR PHARMACEUTICS) etc.
What the people such as Kaneshiro adopted is with benzotriazole-N; N; N '; N '-tetramethyl-urea hexafluorophosphate (HBTU) and I-hydroxybenzotriazole (HOBt) are condensing agent; diisopropyl ethyl amine (N; N-diisopropylethylamine, DIPEA) be alkali, in DMF (DMF), the method for the Methionin dicyclohexyl amine salt condensation of OAS and tertbutyloxycarbonyl (Boc) protection is prepared this dendrimer.The method has four condensations and four deprotection steps, and each condensation step need to be used with respect to the number of amino groups on raw material 3.75 times of excessive HOBt, HBTU and Methionin dicyclohexyl amine salt, and these excessive compounds can cause serious environmental pollution; In addition, the method is long reaction time not only, every step reaction all needs two days about (48 hours), and can form the mashed prod of thickness while reaction mixture being joined in aqueous citric acid solution in post-processing step, this mashed prod cannot filter, and wherein the water-soluble impurity of parcel must could be removed substantially by diffusion repeatedly, the washing of at least 6 times, each 5 hours.This situation causes last handling process length consuming time, complex operation.And the overall yield of this reaction is not high, only have 4.32%.
Summary of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, provide a kind of pollution little, the reaction times is short, and aftertreatment is simple, the synthetic method taking poly-(γ-aminopropyl) silicious sesquioxane of cage modle eight as the dendrimer of core that productive rate is high.
In order to solve the problems of the technologies described above, the technical solution used in the present invention is: a kind of synthetic method taking poly-(γ-aminopropyl) silicious sesquioxane of cage modle eight as the dendrimer trifluoroacetate of core, and synthesis step is as follows:
(1) poly-cage modle eight (γ-aminopropyl) silicious sesquioxane hydrochloride and diisopropyl ethyl amine are dissolved in DMF, stir 20～40min, then dropwise drip the N that is dissolved in DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or be dissolved in the N of DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester, stirring reaction 10～14 hours under room temperature; Adding after completion of the reaction temperature is in the acetonitrile of-2～2 DEG C, filter, under gained solid room temperature vacuum-drying 20～24 hours the G1 (OL) of tertbutyloxycarbonyl protection;
Above-mentioned poly-(γ-aminopropyl) silicious sesquioxane hydrochloride of cage modle eight, diisopropyl ethyl amine, N, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or N, the mol ratio between N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is 1: 16～20: 12～16;
(2) it is in the trifluoroacetic acid of-2～2 DEG C and stirring reaction 3～5 hours that the G1 (OL) of the tertbutyloxycarbonyl protection of being prepared by step (1) method joins temperature, and the concentration of the G1 (OL) of described tertbutyloxycarbonyl protection in trifluoroacetic acid is 0.04～0.06mmol/ml; After completion of the reaction reaction mixture is joined in the ether that is chilled to-2～5 DEG C, mix, leave standstill and filter collecting precipitation, obtain G1 (OL) trifluoroacetate;
(3) G1 (OL) trifluoroacetate and the diisopropyl ethyl amine prepared by step (2) are dissolved in DMF, stir 20～40min, then dropwise drip the N that is dissolved in DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or be dissolved in the N of DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester, stirring reaction 10～14 hours under room temperature; Adding after completion of the reaction temperature is the acetonitrile of-2～2 DEG C, filter, under gained solid room temperature vacuum-drying 20～24 hours the G2 (OL) of tertbutyloxycarbonyl protection;
Above-mentioned G1 (OL) trifluoroacetate, diisopropyl ethyl amine, N, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or N, the mol ratio between N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is 1: 32～40: 24～32;
Then the G2 (OL) of tertbutyloxycarbonyl protection is joined to temperature and be in the trifluoroacetic acid of-2～2 DEG C and stirring reaction 3～5 hours, the concentration of the G2 (OL) of described tertbutyloxycarbonyl protection in trifluoroacetic acid is 0.04～0.06mmol/ml; After completion of the reaction reaction mixture is joined in the ether that is chilled to-2～5 DEG C, mix, leave standstill and filter collecting precipitation, obtain G2 (OL) trifluoroacetate;
(4) G2 (OL) trifluoroacetate and the diisopropyl ethyl amine prepared by step (3) are dissolved in DMF, stir 20～40min, then dropwise drip the N that is dissolved in DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or be dissolved in the N of DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester, stirring reaction 10～14 hours under room temperature; Add after completion of the reaction the acetonitrile of-2～2 DEG C, filter, under gained solid room temperature, vacuum-drying obtains the G3 (OL) of tertbutyloxycarbonyl protection for 20～24 hours;
Above-mentioned G2 (OL) trifluoroacetate, diisopropyl ethyl amine, N, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or N, the mol ratio between N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is 1: 64～80: 48～64;
Then the G3 (OL) of tertbutyloxycarbonyl protection is joined to temperature and be in the trifluoroacetic acid of-2～2 DEG C and stirring reaction 3～5 hours, the concentration of the G3 (OL) of described tertbutyloxycarbonyl protection in trifluoroacetic acid is 0.04～0.06mmol/ml; After completion of the reaction reaction mixture is joined in the ether that is chilled to-2～5 DEG C, mix, leave standstill and filter collecting precipitation, can make G3 (OL) trifluoroacetate;
(5) G3 (OL) trifluoroacetate and the diisopropyl ethyl amine prepared by step (4) are dissolved in DMF, stir 20～40min, then dropwise drip the N that is dissolved in DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or be dissolved in the N of DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester, stirring reaction 10～14 hours under room temperature; Adding after completion of the reaction temperature is in the acetonitrile of-2～2 DEG C, filter, under gained solid room temperature vacuum-drying 20～24 hours the G4 (OL) of tertbutyloxycarbonyl protection;
Above-mentioned G3 (OL) trifluoroacetate, diisopropyl ethyl amine, N, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or N, the mol ratio between N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is 1: 28～160: 96～128;
Then the G4 (OL) of tertbutyloxycarbonyl protection is joined to temperature and be in the trifluoroacetic acid of-2～2 DEG C and stirring reaction 3～5 hours, the concentration of the G4 (OL) of described tertbutyloxycarbonyl protection in trifluoroacetic acid is 0.04～0.06mmol/ml; After completion of the reaction reaction mixture is joined in the ether that is chilled to-2～5 DEG C, mix, leave standstill and filter collecting precipitation, make G4 (OL) trifluoroacetate.
Advantage of the present invention and beneficial effect: the synthetic method taking poly-(γ-aminopropyl) silicious sesquioxane of cage modle eight as the dendrimer trifluoroacetate of core of the present invention, raw material consumption is little, and kind is few, therefore, there is pollution little, reaction times is short, the advantage that aftertreatment is simple, yield is high.
Brief description of the drawings
Fig. 1 is the general structure of dendrimer;
Fig. 2 is G4 (OL) structural diagrams.
Embodiment
Below by embodiment, the present invention is described in further detail, but the present invention is not only confined to following examples.
Embodiment 1
1, by OAS hydrochloride (0.50g, 0.43mmol) and DIPEA (0.89g, 6.88mmol) be dissolved in 20ml DMF, after stirring 30min, dropwise drip the N that is dissolved in 30ml DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester (3.05g, 6.88mmol), stirring reaction 12 hours under room temperature.React the complete 150ml of adding and be refrigerated to the acetonitrile of 0 DEG C, filter, under gained solid room temperature, vacuum-drying obtains the G1 (OL) (1.21g, 0.34mmol) of tertbutyloxycarbonyl protection, productive rate 80% for 24 hours.
2, the G1 (OL) (1.02g, 0.29mmol) of tertbutyloxycarbonyl protection is joined in the trifluoroacetic acid (5ml) that is refrigerated to 0 DEG C and stirring reaction 4 hours.After completion of the reaction reaction mixture is joined in the ether that 50ml is chilled to 0 DEG C, filter collecting precipitation, obtain G1 (OL) trifluoroacetate 0.80g (0.21mmol), productive rate 74%.
3, taking G1 (OL) trifluoroacetate as raw material, by G1 (OL) trifluoroacetate, DIPEA and N, the mol ratio of N '-bis-tertbutyloxycarbonyl-1B N-succimide ester is adjusted into 1: 36: 28, all the other operation repeating step 1 and steps 2, make G2 (OL) trifluoroacetate, productive rate 70%.
4, taking G2 (OL) trifluoroacetate as raw material, by G2 (OL) trifluoroacetate, DIPEA and N, the mol ratio of N '-bis-tertbutyloxycarbonyl-1B N-succimide ester is adjusted into 1: 72: 56, all the other operation repeating step 1 and steps 2, make G3 (OL) trifluoroacetate, productive rate 75%.
5, taking G3 (OL) trifluoroacetate as raw material, by G3 (OL) trifluoroacetate, DIPEA and N, the mol ratio of N '-bis-tertbutyloxycarbonyl-1B N-succimide ester is adjusted into 1: 144: 112, all the other operations repeat repeating step 1 and step 2, make G4 (OL) trifluoroacetate, productive rate 72%.
Embodiment 2
1, by OAS hydrochloride (0.50g, 0.43mmol) and DIPEA (0.89g, 6.88mmol) be dissolved in 20ml DMF, after stirring 30min, dropwise drip the N that is dissolved in 30ml DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester (3.52g, 6.88mmol), stirring reaction 8 hours under room temperature.Add after completion of the reaction 150ml to be refrigerated to the acetonitrile of 0 DEG C, filter, the vacuum-drying of gained solid obtains the G1 (OL) (1.28g, 0.37mmol) of tertbutyloxycarbonyl protection, productive rate 85%.
2, the G1 (OL) (1.02g, 0.29mmol) of tertbutyloxycarbonyl protection is joined in the trifluoroacetic acid (5ml) that is refrigerated to 0 DEG C and stirring reaction 4 hours.After completion of the reaction reaction mixture is joined in the ether that 50ml is chilled to 0 DEG C, filter collecting precipitation, obtain G1 (OL) trifluoroacetate 0.86g (0.23mmol), productive rate 80%.
3, taking G1 (OL) trifluoroacetate as raw material, by G1 (OL) trifluoroacetate, DIPEA and N, the mol ratio of N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is adjusted into 1: 36: 28, all the other operation repeating step 1 and steps 2, make G2 (OL) trifluoroacetate, productive rate 75%.
4, taking G2 (OL) trifluoroacetate as raw material, by G2 (OL) trifluoroacetate, DIPEA and N, the mol ratio of N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is adjusted into 1: 72: 56, all the other operation repeating step 1 and steps 2, can make G3 (OL) trifluoroacetate, productive rate 72%.
5, taking G3 (OL) trifluoroacetate as raw material, by G3 (OL) trifluoroacetate, DIPEA and N, the mol ratio of N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is adjusted into 1: 144: 112, all the other operation repeating step 1 and steps 2, make G4 (OL) trifluoroacetate, productive rate 70%.
From above-described embodiment, method reaction product yield of the present invention is high, and the reaction times is short, and aftertreatment is simple.
Claims (1)
1. a synthetic method taking poly-(γ-aminopropyl) silicious sesquioxane of cage modle eight as the dendrimer trifluoroacetate of core, is characterized in that: synthesis step is as follows:
(1) poly-cage modle eight (γ-aminopropyl) silicious sesquioxane hydrochloride and diisopropyl ethyl amine are dissolved in DMF, stir 20 ~ 40min, then dropwise drip the N that is dissolved in DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or be dissolved in the N of DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester, stirring reaction 10 ~ 14 hours under room temperature; Adding after completion of the reaction temperature is in the acetonitrile of-2 ~ 2 DEG C, filter, under gained solid room temperature vacuum-drying 20 ~ 24 hours the G1(OL of tertbutyloxycarbonyl protection);
Above-mentioned poly-(γ-aminopropyl) silicious sesquioxane hydrochloride of cage modle eight, diisopropyl ethyl amine, N, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or N, the mol ratio between N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is 1:16 ~ 20:12 ~ 16;
(2) G1(OL of the tertbutyloxycarbonyl protection of being prepared by step (1) method) join in the trifluoroacetic acid that temperature is-2 ~ 2 DEG C and stirring reaction 3 ~ 5 hours, the G1(OL of described tertbutyloxycarbonyl protection) concentration in trifluoroacetic acid is 0.04 ~ 0.06mmol/ml; After completion of the reaction reaction mixture is joined in the ether that is chilled to-2 ~ 5 DEG C, mixes, leaves standstill and filter collecting precipitation, obtain G1(OL) trifluoroacetate;
(3) G1(OL being prepared by step (2)) trifluoroacetate and diisopropyl ethyl amine be dissolved in DMF, stir 20 ~ 40min, then dropwise drip the N that is dissolved in DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or be dissolved in the N of DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester, stirring reaction 10 ~ 14 hours under room temperature; Adding after completion of the reaction temperature is the acetonitrile of-2 ~ 2 DEG C, filter, under gained solid room temperature vacuum-drying 20 ~ 24 hours the G2(OL of tertbutyloxycarbonyl protection);
Above-mentioned G1(OL) trifluoroacetate, diisopropyl ethyl amine, N, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or N, the mol ratio between N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is 1:32 ~ 40:24 ~ 32;
Then by the G2(OL of tertbutyloxycarbonyl protection) join in the trifluoroacetic acid that temperature is-2 ~ 2 DEG C and stirring reaction 3 ~ 5 hours, the G2(OL of described tertbutyloxycarbonyl protection) concentration in trifluoroacetic acid is 0.04 ~ 0.06mmol/ml; After completion of the reaction reaction mixture is joined in the ether that is chilled to-2 ~ 5 DEG C, mixes, leaves standstill and filter collecting precipitation, obtain G2(OL) trifluoroacetate;
(4) G2(OL being prepared by step (3)) trifluoroacetate and diisopropyl ethyl amine be dissolved in DMF, stir 20 ~ 40min, then dropwise drip the N that is dissolved in DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or be dissolved in the N of DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester, stirring reaction 10 ~ 14 hours under room temperature; Add after completion of the reaction the acetonitrile of-2 ~ 2 DEG C, filter, under gained solid room temperature, vacuum-drying obtains the G3(OL of tertbutyloxycarbonyl protection for 20 ~ 24 hours);
Above-mentioned G2(OL) trifluoroacetate, diisopropyl ethyl amine, N, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or N, the mol ratio between N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester is 1:64 ~ 80:48 ~ 64;
Then by the G3(OL of tertbutyloxycarbonyl protection) join in the trifluoroacetic acid that temperature is-2 ~ 2 DEG C and stirring reaction 3 ~ 5 hours, the G3(OL of described tertbutyloxycarbonyl protection) concentration in trifluoroacetic acid is 0.04 ~ 0.06mmol/ml; After completion of the reaction reaction mixture is joined in the ether that is chilled to-2 ~ 5 DEG C, mixes, leaves standstill and filter collecting precipitation, can make G3(OL) trifluoroacetate;
(5) G3(OL being prepared by step (4)) trifluoroacetate and diisopropyl ethyl amine be dissolved in DMF, stir 20 ~ 40min, then dropwise drip the N that is dissolved in DMF, N '-bis-tertbutyloxycarbonyl-1B N-succimide ester or be dissolved in the N of DMF, N '-bis-tertbutyloxycarbonyl-1B penta fluoro benzene phenolic ester, stirring reaction 10 ~ 14 hours under room temperature; Adding after completion of the reaction temperature is in the acetonitrile of-2 ~ 2 DEG C, filter, under gained solid room temperature vacuum-drying 20 ~ 24 hours the G4(OL of tertbutyloxycarbonyl protection);
Above-mentioned G3(OL) trifluoroacetate, diisopropyl ethyl amine, N, N-bis-tertbutyloxycarbonyls-1B N-succimide ester or N, the mol ratio between N-bis-tertbutyloxycarbonyls-1B penta fluoro benzene phenolic ester is 1:128 ~ 160:96 ~ 128;
Then by the G4(OL of tertbutyloxycarbonyl protection) join in the trifluoroacetic acid that temperature is-2 ~ 2 DEG C and stirring reaction 3 ~ 5 hours, the G4(OL of described tertbutyloxycarbonyl protection) concentration in trifluoroacetic acid is 0.04 ~ 0.06mmol/ml; After completion of the reaction reaction mixture is joined in the ether that is chilled to-2 ~ 5 DEG C, mixes, leaves standstill and filter collecting precipitation, make G4(OL) trifluoroacetate.
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