CN101891739A - Pyridino-uracil peptide nucleic acid monomer and intermediate thereof as well as preparation method and application of same - Google Patents
Pyridino-uracil peptide nucleic acid monomer and intermediate thereof as well as preparation method and application of same Download PDFInfo
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Abstract
The invention discloses a pyridino-uracil peptide nucleic acid monomer and intermediate thereof as well as preparation method and application of the same. The intermediate is shown as formula I or II in the specification, and the peptide nucleic acid monomer is shown as formula V or VI in the specification. The invention provides a peptide nucleic acid monomer with a novel structure, and provides a new method for synthetizing a disubstituted benzo-uracil peptide nucleic acid monomer. Because the peptide nucleic acid monomer has a different chemical structure, the electrical performance of the peptide nucleic acid monomer is also different so that the peptide nucleic acid monomer can be used for establishing nucleic acid bionic nanophase materials with potential gradients and can be applied to the field of photoelectron.
Description
Technical field
The invention belongs to nucleic acid material and biomimetic material field, relate to a kind of pyridino-uracil class peptide nucleic acid monomer and intermediate thereof and their preparation method and application.
Background technology
(peptide nucleic acid, PNA see document: Nielsen, P.E. to peptide nucleic acid(PNA); Egholm, M.; Berg, R.H.; Buchardt, O., Sequence selective recognition of DNA by strand displacement with a thymine-substitute polyamide, Science, 1991,254,1498～1500) be nucleic acid (DNA) the structural simulation molecule of a quasi-representative, be to be that the class peptide chain that the unit forms has been replaced the phosphide chain of nucleic acid, but kept the base structure of DNA that base is that the peptide nucleic acid(PNA) molecular structure of thymine (T) is suc as formula shown in a with 2-aminoethyl-glycine.Therefore, pna molecule is an electric neutrality, and have good light, heat and a chemical stability, not only have similar molecular recognition of DNA and recognition sequence performance, its recognition sequence performance is stronger than DNA, has important application prospects at gene therapy, gene test, gene silencing aspects such as (silence), therefore, since 1991 by since people such as the Peter Nielsen invention, obtained chemical boundary and the experts and scholars' of molecular biosciences educational circles great attention, and obtained significant progress.
(formula a)
(formula b)
(formula c)
Be to be the synthetic route of the peptide nucleic acid monomer of representative shown in the formula c with base T (1), on 1, insert the acetate unit and form compound 2, compound 2 forms compound 4 posthydrolysiss with compound 3 reactions and obtains peptide nucleic acid monomer 5,5th, can be directly used in the monomer of solid phase synthesis.Document (L.Kospkina, W.T.WeiWang and T.C.Liang, Tetrahedron Lett. are arranged, 1994,35,5173-5176 and A.R.Katritzky, T.Narindoshvili, Org.Biomol.Chem., 2008,6,3171-3176) report, compound 2 can obtain by single step reaction in the aqueous solution of potassium hydroxide (KOH) by compound 1 and bromoacetic acid, and productive rate is 50-80%.Other synthetic method comprises: at N, in the dinethylformamide (DMF), with salt of wormwood (K
2CO
3) be alkali, catalysis 1 and ethyl bromoacetate, and further the ethyl ester hydrolysis can be obtained product 2, productive rate is 30-70% (K.L.Dueholm, M.Egholm, C.Behrens, L.Christensen, H.F.Hansen, T.Vulpius, K.H.Petersen, R.H.Berg, P.E.Niesen, O, Buchardt, J.Org.Chem.1994,59,5767-5773).Above-mentioned test method is applicable to natural base T and is prepared peptide nucleic acid monomer as raw material.But for the base (formula b) of pyridino-uracil class, aforesaid method can not obtain the peptide nucleic acid monomer of higher yields.
Summary of the invention
The purpose of this invention is to provide a kind of pyridino-uracil class peptide nucleic acid monomer and intermediate thereof and their preparation method and application.
The intermediate of preparation pyridino-uracil class peptide nucleic acid monomer provided by the invention is formula I or the described compound of formula II general structure,
(formula I)
(formula II)
In described formula I and the formula II general structure, R is-F ,-Cl ,-Br ,-I ,-H ,-CH
3,-CH
2CH
3Or-CH
2CH
2CH
3
The method of the described compound of preparation formula I provided by the invention comprises the steps:
1) analog derivative of pyridino-uracil shown in the formula III is reacted with sodium hydroxide in organic solvent, reaction finishes and obtains reaction soln A;
(formula III)
In the described formula III, R is-F ,-Cl ,-Br ,-I ,-H ,-CH
3,-CH
2CH
3Or-CH
2CH
2CH
3
2) bromoacetic acid is dissolved in the organic solvent, obtains reaction soln B, described reaction soln B and described reaction soln A are reacted, obtain the described compound of formula I.
In the step 1) of this method, described organic solvent is selected from dimethyl sulfoxide (DMSO) and N, at least a in the dinethylformamide, preferred dimethyl sulfoxide (DMSO); The amount ratio of pyridino-uracil analog derivative, sodium hydroxide and described organic solvent shown in the described formula III is 1mmol: 2-10mmol: 2-10ml, specifically can be 1mmol: 2.3-9.3mmol: 3.3-4.9ml, 1mmol: 4.6-8.5mmol: 3.3-4.9ml or 1mmol: 2.3-9.3mmol: 3.3-4.1ml; Temperature is 20-80 ℃, specifically can be 20-70 ℃, 20-40 ℃ or 40-70 ℃, and preferred 20-70 ℃, the time is 10-300 minute, preferred 100-200 minute;
Described step 2) in, described organic solvent is selected from dimethyl sulfoxide (DMSO) and N, at least a in the dinethylformamide, preferred dimethyl sulfoxide (DMSO); The amount ratio of described bromoacetic acid and described organic solvent is 1-1.5mmol: 0.05-0.3ml, specifically can be 1mmol: 0.066-0.22ml or 1mmol: 0.12-0.18ml; In the described reactions steps, temperature is 20-80 ℃, and preferred 20-70 ℃, the time is 5-1 5 hours, preferred 10 hours.
In described step 2) reaction finish after, reaction system is carried out following purification process:
With reaction system and ethyl acetate mixing, collect the precipitation obtain, described precipitation is soluble in water, regulate pH value to 2, obtain compound shown in the formula I behind the purifying.Wherein, ethyl acetate can determine that the consumption of water can be determined according to the resolution of precipitate situation according to the sedimentary situation of separating out.
In addition, in the described step 1) reactant R be-formula III of H shown in the pyridino-uracil analog derivative, be according to following method preparation and get:
With commercially available 2-amino-3-carboxyl-pyridine (4.14g, 30mmol) and urea (18g 300mmol) is blended in the round-bottomed flask of a 100mL, 160 ℃ of following heated overnight cool to 100 ℃, add 50mL water, stir after 30 minutes, filter, collecting precipitation obtains described product.
The method of the described compound of preparation formula II provided by the invention comprises the steps:
1) pyridino-uracil analog derivative shown in the formula IV is reacted with sodium hydroxide in organic solvent, reaction finishes and obtains reaction soln A;
(formula IV)
Among the described formula IV, R is-F ,-Cl ,-Br ,-I ,-H ,-CH
3,-CH
2CH
3Or-CH
2CH
2CH
3
2) bromoacetic acid is dissolved in the organic solvent, obtains reaction soln B, described reaction soln B and described reaction soln A are reacted, obtain the described compound of formula II.
In the step 1) of this method, described organic solvent is selected from dimethyl sulfoxide (DMSO) and N, at least a in the dinethylformamide, preferred dimethyl sulfoxide (DMSO); The amount ratio of pyridino-uracil analog derivative, sodium hydroxide and described organic solvent shown in the described formula IV is 1mmol: 2-10mmol: 2-10ml, specifically can be 1mmol: 2.3-4.6mmol: 4.1-4.9ml or 1mmol: 3.7-4.6mmol: 4.1-4.9ml; Temperature is 20-80 ℃, specifically can be 20-70 ℃, 20-40 ℃ or 40-70 ℃, and preferred 20-70 ℃, the time is 10-300 minute, preferred 100-200 minute;
Described step 2) in, described organic solvent is selected from dimethyl sulfoxide (DMSO) and N, at least a in the dinethylformamide, preferred dimethyl sulfoxide (DMSO); The amount ratio of described bromoacetic acid and described organic solvent is 1-1.5mmol: 0.1-1.0ml, is specially 1mmol: 0.17-0.66ml, 1mmol: 0.17-0.22ml or 1mmol: 0.22-0.66ml; In the described reactions steps, temperature is 20-80 ℃, and preferred 20-70 ℃, the time is 5-15 hour, preferred 10 hours.
In described step 2) reaction finish after, reaction system is carried out following purification process:
With reaction system and ethyl acetate mixing, collect the precipitation obtain, described precipitation is soluble in water, regulate pH value to 2, obtain compound shown in the formula II behind the purifying.Wherein, ethyl acetate can determine that the consumption of water can be determined according to the resolution of precipitate situation according to the sedimentary situation of separating out.
In addition, in the described step 1) reactant R be-the formula IV of H shown in the pyridino-uracil analog derivative, be according to following method preparation and get:
With commercially available 2-amino-3-carboxyl-pyridine (4.14g, 30mmol) and urea (18g 300mmol) is blended in the round-bottomed flask of a 100mL, 160 ℃ of following heated overnight cool to 100 ℃, add 50mL water, stir after 30 minutes, filter, collecting precipitation obtains described product.
Peptide nucleic acid monomer compound provided by the invention, its general structure be suc as formula peptide nucleic acid monomer compound shown in V or the formula VI,
(formula V)
(formula VI)
Among described formula V and the formula VI, R is-F ,-Cl ,-Br ,-I ,-H ,-CH
3,-CH
2CH
3Or-CH
2CH
2CH
3
The method of the above-mentioned peptide nucleic acid monomer compound of preparation provided by the invention comprises the steps:
With compound shown in formula I or the formula II and and benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) is dissolved among the organic solvent a and N, after the N-diisopropylethylamine at room temperature reacts 10-30 minute, add N-tert.-butoxy-carbonyl-1 again, the organic solution of 2-diaminoethanes is at room temperature reacted after 60-240 minute and is obtained product a, described product a at room temperature reacted 30-120 minute with sodium hydroxide in organic liquid mixture after, regulate the pH value to 3-5, obtain described peptide nucleic acid monomer compound; The organic solution of described N-tert.-butoxy-carbonyl-1 is described N-tert.-butoxy-carbonyl-1 is dissolved among the organic solvent b and gets.Wherein, be the described peptide nucleic acid monomer of formula V with compound products therefrom shown in the formula I; With compound products therefrom shown in the formula II is the described peptide nucleic acid monomer of formula VI.
In the aforesaid method, described organic solvent a and organic solvent b all are selected from N, at least a in dinethylformamide and the methyl-sulphoxide, preferred N, dinethylformamide; Described organic liquid mixture is to be that 1: 1 methylene dichloride mixes with ethanol and gets by volume ratio; Described formula I or the described compound of formula II, benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate, organic solvent a, N, N-diisopropylethylamine, N-tert.-butoxy-carbonyl-1,2-diaminoethanes, organic solvent b: the amount ratio of sodium hydroxide is 1mmol: 1-1.32mmol: 0.5-6ml: 1-1.32mmol: 1-1.32mmol: 0.5-6ml: 1-3mmol, preferred 1mmol: 1mmol: 2ml: 1mmol: 1mmol: 2ml: 2mmol or 1mmol: 1.32mmol: 6ml: 1.32mmol: 1.32mmol: 6ml: 2.4mmol.Described room temperature is 10-25 ℃.
In addition, peptide nucleic acid monomer compound shown in formula V or the formula VI has application in the nucleic acid bionic material of electric potential gradient in preparation, and is the peptide nucleic acid(PNA) that monomer prepares with peptide nucleic acid monomer compound shown in formula V or the formula VI, also belongs to protection scope of the present invention.This peptide nucleic acid(PNA) is to be carried out condensation reaction preparation and got by the compound of peptide nucleic acid monomer shown in the formula III.Described nucleic acid bionic material with electric potential gradient is preferably biological organic photovoltaic battery.
The invention provides a kind of peptide nucleic acid monomer of novel texture, and the novel method of a kind of synthetic such disubstituted benzenes and uracil peptide nucleic acid monomer is provided.Because this peptide nucleic acid monomer has different chemical structures, its electrical property is also different, thereby, can be used for making up nucleic acid bionic nano material with electric potential gradient, be applied to optoelectronic areas.
Description of drawings
Fig. 1 prepares the nucleus magnetic hydrogen spectrum and the carbon spectrum of gained intermediate for embodiment 1-4.
Fig. 2 prepares the nucleus magnetic hydrogen spectrum and the carbon spectrum of gained intermediate for embodiment 5-8.
Fig. 3 is the nucleus magnetic hydrogen spectrum and the carbon spectrum of embodiment 9 preparation gained peptide nucleic acid monomers.
Fig. 4 is the nucleus magnetic hydrogen spectrum and the carbon spectrum of embodiment 10 preparation gained peptide nucleic acid monomers.
Embodiment
Be described further below in conjunction with the effect of specific embodiment, but the present invention is not limited to following examples solvent among the present invention and temperature.If no special instructions, described method is ordinary method in the following method.
The intermediate (compound 3) of the peptide nucleic acid monomer of pyridino-uracil class shown in embodiment 1, the preparation formula I
1) under 30 ℃ heating condition, (4g 24.5mmol) is dissolved among 120 milliliters the DMSO, and (2.3g, 56.8mmol), under 30 ℃ heating condition, stirring reaction 1 hour obtains reaction soln (A) to add NaOH with compound 2 pyridino-uracils.
2) (3.16g 22.71mmol) is dissolved among 5 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under 30 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 12 hours.Reaction solution is poured in 150 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 50 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 1.5 gram (9.2mmol) compounds 2, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 1.1 gram (5.0mmol) product compounds 3, productive rate 20%.
It is as follows that the nuclear-magnetism of this product detects data:
1H-NMR(400MHz，DMSO-d
6)δ：13.06(s，1H，-NH)，11.48(s，1H，-NH)，8.70(d，1H，J＝8.0Hz，-pyH)，8.26(d，1H，J＝8.0Hz，-pyH)，7.28(q，1H，J＝4.8?and?6.8Hz，-pyH)，4.53(s，2H，-CH
2)，3.30(s，3H，-CH
3)；
13C?NMR(DMSO-d
6，100MHz)δ：169.4，162.2，152.5，151.8，149.3，135.7，126.5，117.2，41.2；GCT-MS?m/z(％)：221.0(M，100％)。
The nucleus magnetic hydrogen spectrum of this product and carbon spectrum are as shown in Figure 1.As from the foregoing, this compound structure is correct, is the intermediate (compound 3) of the peptide nucleic acid monomer of benzo uracil shown in the formula I.
Wherein, used reactant compound 2 pyridino-uracils are to be prepared as follows and to get in the aforesaid method step 1):
With commercially available 2-amino-3-carboxyl-pyridine (4.14g, 30mmol, compound 1) and urea (18g 300mmol) is blended in the round-bottomed flask of a 100mL, 160 ℃ of following heated overnight, cool to 100 ℃, add 50mL water, stir after 30 minutes, filter, collecting precipitation obtain compound 2 (2.5g, 15.33mmol), productive rate 51%.The structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 11.64 (s, 1H ,-NH), 11.48 (s, 1H ,-NH), 8.60 (d, 1H, J=8.0Hz ,-pyH), 8.26 (d, 1H, J=8.0Hz ,-pyH), 7.26 (q, 1H, J=4.8and 6.8Hz ,-pyH), 3.30 (s, 3H ,-CH
3);
13C NMR (DMSO-d
6, 100MHz) δ: 162.2,154.8,151.3,150.4,135.7,126.5,110.2,20.2; GCT-MS m/z (%): 163.0 (M, 100%).As from the foregoing, this compound structure is correct, is compound 2 pyridino-uracils.
The intermediate (compound 3) of the peptide nucleic acid monomer of pyridino-uracil class shown in embodiment 2, the preparation formula I
1) under 50 ℃ heating condition, (4g 24.5mmol) is dissolved among 100 milliliters the DMSO, and (4.6g, 113.6mmol), under 50 ℃ heating condition, stirring reaction 2 hours obtains reaction soln (A) to add NaOH with described compound 2 pyridino-uracils.
2) (6.32g 45.4mmol) is dissolved among 3 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under 50 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 16 hours.Reaction solution is poured in 150 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 70 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 1.8 gram (11.0mmol) compounds 2, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.8 gram (3.6mmol) product compound 3, productive rate 15%.
The nuclear-magnetism of this product detects data with embodiment 1.As from the foregoing, this compound structure is correct, is the intermediate (compound 3) of the peptide nucleic acid monomer of benzo uracil shown in the formula I.
The intermediate (compound 3) of the peptide nucleic acid monomer of pyridino-uracil class shown in embodiment 3, the preparation formula I
1) under 80 ℃ heating condition, (4g 24.5mmol) is dissolved among 80 milliliters the DMSO, and (1.84g, 45.4mmol), under 80 ℃ heating condition, stirring reaction 3 hours obtains reaction soln (A) to add NaOH with compound 2 pyridino-uracils.
2) (4.74g 34.1mmol) is dissolved among 4 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under 80 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 24 hours.Reaction solution is poured in 150 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 60 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 1.3 gram (7.9mmol) compounds 2, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.95 gram (4.3mmol) product compound 3, productive rate 17.5%.
The nuclear-magnetism of this product detects data with embodiment 1.As from the foregoing, this compound structure is correct, is the intermediate (compound 3) of the peptide nucleic acid monomer of benzo uracil shown in the formula I.
The intermediate (compound 3) of the peptide nucleic acid monomer of pyridino-uracil class shown in embodiment 4, the preparation formula I
1) under 40 ℃ heating condition, (4g 24.5mmol) is dissolved among 120 milliliters the DMF, and (4.5g, 113.55mmol), under 40 ℃ heating condition, stirring reaction 1 hour obtains reaction soln (A) to add NaOH with compound 2 pyridino-uracils.
2) (3.79g 27.2mmol) is dissolved among 5 milliliters of DMF, obtains reaction soln (B) with bromoacetic acid.Under 40 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 12 hours.Reaction solution is poured in 150 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 150 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 2.0 gram (12.3mmol) compounds 2, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.6 gram (2.7mmol) product compound 3, productive rate 11%.
The nuclear-magnetism of this product detects data with embodiment 1.As from the foregoing, this compound structure is correct, is the intermediate (compound 3) of the peptide nucleic acid monomer of benzo uracil shown in the formula I.
The intermediate (compound 6) of the peptide nucleic acid monomer of pyridino-uracil class shown in embodiment 5, the preparation formula II
1) under 20 ℃ heating condition, pyridino-uracil (4g, 24.5mmol, compound 5) is dissolved among 100 milliliters the DMSO, (9.0g, 227.1mmol), under 20 ℃ heating condition, stirring reaction 3 hours obtains reaction soln (A) to add NaOH.
2) (3.48g 24.9mmol) is dissolved among 3 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under 20 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 10 hours.Reaction solution is poured in 130 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 130 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 1.5 gram (9.2mmol) compounds 5, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.81 gram (3.7mmol) product compound 6, productive rate 15%.
It is as follows that the nuclear-magnetism of this product detects data:
1H-NMR(400MHz，DMSO-d
6)δ：13.04(s，1H，-NH)，11.48(s，1H，-NH)，8.60(d，1H，J＝8.0Hz，-pyH)，8.30(d，1H，J＝8.0Hz，-pyH)，7.31(q，1H，J＝4.8?and?6.8Hz，-pyH)，4.53(s，2H，-CH
2)，3.30(s，3H，-CH
3)；
13C?NMR(DMSO-d
6，100MHz)δ：169.4，161.9，154.8，151.3，149.4，135.7，118.5，114.2，41.2；GCT-MS?m/z(％)：221.0(M，100％)。
The nucleus magnetic hydrogen spectrum of this product and carbon spectrum are as shown in Figure 2.As from the foregoing, this compound structure is correct, is the intermediate (compound 6) of the peptide nucleic acid monomer of benzo uracil shown in the formula I.
Wherein, used reactant compound 5 pyridino-uracils are to be prepared as follows and to get in the aforesaid method step 1):
With commercially available 2-amino-3-carboxyl-pyridine (4.14g, 30mmol, compound 4) and urea (18g 300mmol) is blended in the round-bottomed flask of a 100mL, 160 ℃ of following heated overnight, cool to 100 ℃, add 50mL water, stir after 30 minutes, filter, collecting precipitation obtain compound 5 (3.5g, 21.5mmol), productive rate 71%.
The structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 11.64 (s, 1H ,-NH), 11.48 (s, 1H ,-NH), 8.60 (d, 1H, J=8.0Hz ,-pyH), 8.30 (d, 1H, J=8.0Hz ,-pyH), 7.31 (q, 1H, J=4.8 and 6.8Hz ,-pyH), 3.30 (s, 3H ,-CH
3);
13C NMR (DMSO-d
6, 100MHz) δ: 162.2,154.8,151.3,150.4,135.7,126.5,110.2,20.2; GCT-MS m/z (%): 163.0 (M, 100%).As from the foregoing, this compound structure is correct, is compound 5.
The intermediate (compound 6) of the peptide nucleic acid monomer of pyridino-uracil class shown in embodiment 6, the preparation formula II
1) under 40 ℃ heating condition, pyridino-uracil (4g, 24.5mmol that embodiment 6 is prepared, compound 5) be dissolved among 120 milliliters the DMSO, add NaOH (2.3g, 56.8mmol), under 40 ℃ heating condition, stirring reaction 1 hour obtains reaction soln (A).
2) (3.16g 22.71mmol) is dissolved among 5 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under 40 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 12 hours.Reaction solution is poured in 150 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 50 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 1.3 gram (8.0mmol) compounds 2, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 1.0 gram (4.5mmol) product compounds 6, productive rate 18.5%.
The nuclear-magnetism of this product detects data with embodiment 5.As from the foregoing, this compound structure is correct, is the intermediate (compound 6) of the peptide nucleic acid monomer of benzo uracil shown in the formula I.
The intermediate (compound 6) of the peptide nucleic acid monomer of pyridino-uracil class shown in embodiment 7, the preparation formula II
1) under 60 ℃ heating condition, pyridino-uracil (4g, 24.5mmol that embodiment 6 is prepared, compound 5) be dissolved among 100 milliliters the DMSO, add NaOH (4.6g, 113.6mmol), under 60 ℃ heating condition, stirring reaction 2 hours obtains reaction soln (A).
2) (6.32g 45.4mmol) is dissolved among 3 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under 60 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 16 hours.Reaction solution is poured in 150 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 70 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 1.6 gram (9.8mmol) compounds 5, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.7 gram (3.2mmol) product compound 6, productive rate 13%.
The nuclear-magnetism of this product detects data with embodiment 5.As from the foregoing, this compound structure is correct, is the intermediate (compound 6) of the peptide nucleic acid monomer of benzo uracil shown in the formula I.
The intermediate (compound 6) of the peptide nucleic acid monomer of pyridino-uracil class shown in embodiment 8, the preparation formula II
1) under 30 ℃ heating condition, with pyridino-uracil (4g, the 24.5mmol for preparing among the embodiment 6, compound 5) be dissolved among 100 milliliters the DMF, add NaOH (3.6g, 90.8mmol), under 30 ℃ heating condition, stirring reaction 3 hours obtains reaction soln (A).
2) (2.53g 18.17mmol) is dissolved among 3 milliliters of DMF, obtains reaction soln (B) with bromoacetic acid.Under 30 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 10 hours.Reaction solution is poured in 130 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 130 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 2.5 gram (15.3mmol) compounds 5, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.41 gram (1.8 mmol) product compound 6, productive rate 7.6%.
The nuclear-magnetism of this product detects data with embodiment 5.As from the foregoing, this compound structure is correct, is the intermediate (compound 6) of the peptide nucleic acid monomer of benzo uracil shown in the formula I.
Peptide nucleic acid monomer shown in embodiment 9, the preparation formula V (compound 9)
1) intermediate of pyridino-uracil class peptide nucleic acid monomer shown in the formula I that embodiment 1-4 is prepared (compound 3) (111mg, 0.5mmol), HBTU (170mg, 0.5mmol) be mixed in 1 milliliter N, in the dinethylformamide (DMF), add N, and the N-diisopropyl ethyl amine (DIEA, 0.5mmol).Stir after 30 minutes, add compound 7 (120mg, 1 milliliter of DMF solution 0.5mmol), after the stirring at room 3 hours, pour in 20 ml waters, collecting precipitation is after ethyl acetate washing, extraction, the organic layer anhydrous magnesium sulfate drying, the oily matter of removing behind the organic solvent is crossed post with silica gel, and using by volume ratio is the mixed solution drip washing that 10: 1 methylene dichloride and ethyl acetate are formed, and obtains product compound 8 (208mg, 0.46mmol), productive rate 90%.
2) product compound 8 being dissolved in volume ratio is in 1: 15 milliliters of the mixed solvents of being made up of methylene dichloride and ethanol, adds the sodium hydroxide of 1 mmole, stirring at room 2 hours, the back neutralizes with 1N hydrochloric acid, the pH value of regulator solution is removed organic solvent and is obtained compound 9 to 3-5, and productive rate is 100%.
It is as follows that the nuclear-magnetism of this compound 9 detects data:
1H-NMR (400MHz, DMSO-d
6) δ: 13.03 (s, 1H ,-OH), 11.46 (s, 1H ,-NH), 8.70 (d, 1H, J=8.0Hz ,-pyH), 8.30 (d, 1H, J=8.0Hz ,-pyH), 7.31 (q, 1H, J=4.8 and 6.8Hz ,-pyH), 6.5 (s, 1H ,-NH), 4.55 (s, 2H ,-CH
2), 3.85 (s, 2H ,-CH
2), 3.0 (m, 2H ,-CH
2), 2.5 (m, 2H ,-CH
2), 1.37 (s, 9H ,-Boc-H);
13C NMR (DMSO-d
6, 100MHz) δ: 169.3,168.1,162.2,160.7,154.8,151.3,150.4,135.7,118.5,114.2,80.5,54.2,52.8,49.8,42.3,28.6; ESI-MS m/z (%): 420.0 (M-H
-, 100%).
The nucleus magnetic hydrogen spectrum of this product and carbon spectrum are as shown in Figure 3.As from the foregoing, this compound structure is correct, is the uracil of benzo shown in formula III peptide nucleic acid monomer (compound 9).
Peptide nucleic acid monomer shown in embodiment 10, the preparation formula VI (compound 11)
1) intermediate of pyridino-uracil class peptide nucleic acid monomer shown in the formula II that embodiment 5-8 is prepared (compound 6) (111mg, 0.5mmol), HBTU (224.4mg, 0.66mmol) be mixed in 3 milliliters N, in the dinethylformamide (DMF), add N, and the N-diisopropyl ethyl amine (DIEA, 0.66mmol).Stir after 40 minutes, add compound 7 (144mg, 3 milliliters of DMF solution 0.66mmol), after the stirring at room 5 hours, pour in 30 ml waters, collecting precipitation is after ethyl acetate washing, extraction, the organic layer anhydrous magnesium sulfate drying, the oily matter of removing behind the organic solvent is crossed post with silica gel, and using by volume ratio is the mixed solution drip washing that 10: 1 methylene dichloride and ethyl acetate are formed, and obtains product compound 10 (188mg, 0.42mmol), productive rate 84%.
2) product compound 10 being dissolved in volume ratio is in 1: 16 milliliters of the mixed solvents of being made up of methylene dichloride and ethanol, the sodium hydroxide that adds 1.2 mmoles, stirring at room 3 hours, the back neutralizes with 1N hydrochloric acid, the pH value of regulator solution is to 3-5, remove organic solvent and obtain compound 11, productive rate is 100%.
It is as follows that the nuclear-magnetism of this compound 11 detects data:
1H-NMR(400MHz，DMSO-d
6)δ：13.08(s，1H，-OH)，11.49(s，1H，-NH)，8.71(d，1H，J＝8.0Hz，-pyH)，8.28(d，1H，J＝8.0Hz，-pyH)，7.28(q，1H，J＝4.8?and?6.8Hz，-pyH)，6.5(s，1H，-NH)，4.55(s，2H，-CH
2)，3.85(s，2H，-CH
2)，3.0(m，2H，-CH
2)，2.5(m，2H，-CH
2)，1.37(s，9H，-Boc-H)；
13C?NMR(DMSO-d
6，100MHz)δ：169.3，168.5，160.7，154.4，152.2，148.7，138.7，135.2，117.6，115.3，80.5，54.2，52.8，49.8，42.3，28.6；ESI-MS?m/z(％)：420.0(M-H
-，100％)。
The nucleus magnetic hydrogen spectrum of this product and carbon spectrum are as shown in Figure 4.As from the foregoing, this compound structure is correct, is the uracil of benzo shown in formula III peptide nucleic acid monomer (compound 11).
Embodiment 11, has the peptide nucleic acid nano heterojunction 1 of electric potential gradient with the preparation of embodiment 9 preparation gained peptide nucleic acid monomers: preparation Pc-R
2-CONH-AAAAA-CONH-R
1-PDI-R
1-CONH-T
Py-8UTT
φT
Na-CONH
2(T
φIn substituent R=-CH
3, T
NaAnd T
Py-8In substituent R be H) peptide nucleic acid nano heterojunction 1
1) is start element with 4-toluene hydrogen amine (mbha resin),, handles 3 times that each 3 minutes is that 1: 1 DMF/DCM washes 3 times with the 2mL mol ratio respectively then, after the 2mL pyridine is washed twice, is T with base with 2mL trifluoroacetic acid (TFA) with after the methylene dichloride swelling
Py-8Peptide nucleic acid monomer activate with dehydration catalyst and diisopropyl ethyl amine after, with mbha resin in 125 μ L N, react in the dinethylformamide (DMF), use the DMF washed twice, with capping reagent (diacetyl oxide) handle and washing after, obtain MBHA-T
Py-8Compound;
2) with described MBHA-T
Py-8Compound and base are that the peptide nucleic acid monomer of U carries out dehydration reaction, obtain MBHA-T
Py-8The U compound;
3) repeating said steps 2) (3) inferior, obtains MBHA-T
Py-8UTT
φT
NaCompound;
4) PDI is activated with dehydration catalyst and diisopropyl ethyl amine after, with described MBHA-T
Py-8UTT
φT
NaCompound reacts, and obtains MBHA-T
Py-8UTT
φT
Na-R
1-PDI compound;
5) be A with base
1Peptide nucleic acid monomer activate with dehydration catalyst and diisopropyl ethyl amine after, with described MBHA-T
Py-8UTT
φT
Na-R
1-PDI compound reacts, and obtains MBHA-T
Py-8UTT
φT
Na-R
1-PDI-R
1-A
1Compound;
6) with described MBHA-T
Py-8UTT
φT
Na-R
1-PDI-R
1-A
1Compound and base are A
2Peptide nucleic acid monomer carry out dehydration reaction, obtain MBHA-T
Py-8UTT
φT
Na-R
1-PDI-R
1-A1A
2Compound;
7) repeating said steps 6) 3 times, obtain MBHA-T
Py-8UTT
φT
Na-R
1-PDI-R
1-A
1A
2A
nCompound;
8) Pc is activated with dehydration catalyst and diisopropyl ethyl amine after, with described MBHA-T
Py-8UTT
φT
Na-R
1-PDI-R
1-A
1A
2A
nCompound reacts, and obtains MBHA-T
Py-8UTT
φT
Na-R
1-PDI-R
1-A
1A
2A
n-R
2-Pc;
9) with described MBHA-T
Py-8UTT
φT
Na-R
1-PDI-R
1-A
1A
2A
n-R
2-Pc and 5mL trifluoroacetic acid and 5mL TFMSA react respectively, and use the ethyl acetate post precipitation, and collecting precipitation obtains unpurified described peptide nucleic acid nano heterojunction molecule.
Above-mentioned unpurified peptide nucleic acid nano heterojunction molecule is dissolved among the 0.5mL DMF, is injected in the high pressure liquid chromatograph (HPLC), use TFA/H
2O (volume ratio 0.5%) and CH
3CN/H
2The mixed solvent wash-out of O (volume ratio 0.5%) is collected elutriant, determine required product with mass spectrum (TOF-MS) after, lyophilize, the gained solid detects with HPLC and TOF-MS again, is defined as target product, i.e. Pc-R
2-CONH-AAAAA-CONH-R
1-PDI-R
1-CONH-T
Py-8UTT
φT
Na-CONH
2(T
NaT
φT
Py-8In substituent R=-CH3), be the peptide nucleic acid(PNA) molecule that a covalent coupling has PDI and Pc;
10) being dissolved in by 50 μ L water and 50 μ L concentration by the peptide nucleic acid(PNA) molecule of PDI and Pc the covalent coupling that obtains in the described step 9) is in the mixed solution formed of the NaCl aqueous solution of 200mM/L, place 37 ℃ incubator to cultivate 2 hours, obtain the described PNA of formula I and be-CONH-Tn-CONH
2Peptide nucleic acid nano heterojunction 1.
In described step 1)-step 9), described reaction is reaction with same mole, and in the step 1), described base is T as described
1The mol ratio of peptide nucleic acid monomer, dehydration catalyst, diisopropyl ethyl amine and 4-toluene hydrogen amine (MBHA) resin be 1: 1: 1: 1.In each reactions steps, the consumption of organic solvent is as the criterion with complete solubilizing reaction thing; Described dehydration catalyst is benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate.
This peptide nucleic acid nano heterojunction 1 can prepare biological organic photovoltaic battery according to ordinary method, and its preparation method is as follows:
Handling on the clean ito glass surface, after spin coating one layer thickness is the PSS/PEDOT (the poly-p styrene sulfonic acid of poly-dioxoethyl thiophene) of 40nm, 150 ℃ of dryings after 0.5 hour, be spin-coated on this PSS/PEDOT layer in the mixture that the peptide nucleic acid nano heterojunction 2 that this embodiment is prepared and oil of mirbane are formed, obtain the active coating (thickness is 100nm) of biological organic photovoltaic battery, after 1 hour, is 5 * 10 in vacuum tightness in 100 ℃ of dryings
-5Under the condition of Pa, evaporation one layer thickness is the metal aluminium electrode of 150nm, obtains described biological organic photovoltaic battery.
In this method, described base is T
φ(R is-CH
3) peptide nucleic acid(PNA) be compound 9
φ, be to be prepared as follows and to get:
1) with midbody compound 2
φ(117mg, 0.5mmol), HBTU (170mg 0.5mmol) is mixed in 1 milliliter N, in the dinethylformamide (DMF), adds N, and the N-diisopropyl ethyl amine (DIEA, 0.5mmol).Stir after 30 minutes, add compound 7
φN-tert.-butoxy-carbonyl-1,2-diaminoethanes (120mg, 0.5mmol) 1 milliliter of DMF solution, stirring at room was poured in 20 ml waters after 2 hours, collecting precipitation, after ethyl acetate washing, extraction, the organic layer anhydrous magnesium sulfate drying, the oily matter of removing behind the organic solvent is crossed post with silica gel, using by volume ratio is the mixed solution drip washing that 10: 1 methylene dichloride and ethyl acetate are formed, and obtains product compound 8
φ(184mg, 0.41mmol), productive rate is 80%.2) with product compound 8
φBe dissolved in volume ratio and be in 1: 15 milliliters of the mixed solvents of being made up of methylene dichloride and ethanol, add the sodium hydroxide of 1 mmole, stirring at room after 2 hours with the neutralization of 1N hydrochloric acid, remove organic solvent and obtain compound 9 to 3-5 by the pH value of regulator solution
φ, productive rate is 100%.The nuclear-magnetism structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 12.99 (s, 1H ,-OH), 11.49 (s, 1H ,-NH), 7.74 (s, 1H ,-phH), 7.53 (d, 1H, J=8.0Hz ,-phH), 7.13 (d, 1H, J=8.0Hz ,-phH), 6.7 (s, 1H ,-NH), 4.55 (s, 2H ,-CH
2), 3.0 (d, 2H, J=5.6Hz ,-CH
2), 2.5 (m, 3H ,-CH
2), 2.35 (s, 3H ,-CH
3), 2.1 (s, 1H ,-CH
2), 1.37 (s, 9H ,-Boc-H);
13C NMR (DMSO-d
6, 100MHz) δ: 169.3,169.1,160.7,155.4,150.2,137.7,136.7,132.8,127.6,125.3,114.2,80.5,54.2,52.8,49.8,42.3,28.6,20.2; ESI-MS m/z (%): 433.0 (M-H
-, 100%).As from the foregoing, this compound structure is correct, is the uracil of benzo shown in formula III peptide nucleic acid monomer (compound 9
φ).
Wherein, described midbody compound 2
φBe to be prepared as follows and to get:
1) under 20 ℃ heating condition, with benzo uridylic (4g, 22.7mmol, compound 1
φ) be dissolved among 120 milliliters the DMSO, (4.5g, 113.55mmol), under the heating condition of 40C, stirring reaction 1 hour obtains reaction soln (A) to add NaOH.2) (3.16g 22.71mmol) is dissolved among 5 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under the heating condition of 40C, reaction soln B is joined among the reaction soln A, after adding, continued stirring reaction 12 hours.Reaction solution is poured in 150 milliliters of ethyl acetate, collected the precipitation obtain, precipitation is dissolved in 150 ml waters, to pH=7, filter and obtain 1.5 and restrain (8.5mmol) compounds 1 with the pH value of 6N hydrochloric acid conditioning solution
φ, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 1.1 gram (2.3mmol) product compounds 2
φ, productive rate is 10%.The nuclear-magnetism structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 12.99 (s, 1H ,-OH), 11.49 (s, 1H ,-NH), 7.74 (s, 1H ,-phH), 7.53 (d, 1H, J=8.0Hz ,-phH), 7.13 (d, 1H, J=8.0Hz ,-phH), 4.55 (s, 2H ,-CH
2), 2.35 (s, 3H ,-CH
3);
13CNMR (DMSO-d
6, 100MHz) δ: 169.4,161.6,149.8,137.2,136.4,132.1,126.8,115.3,113.2,41.3,20.2; ESI-MS m/z (%): 233.0 (M-H
-, 100%).As from the foregoing, this compound structure is correct, is the intermediate (compound 2 of the peptide nucleic acid monomer of benzo uracil shown in the formula I
φ).
Wherein, the used reactant compound 1 of step 1)
φBe to be prepared as follows and to get: with commercially available 2-amino-5 methyl-phenylformic acid (4.5g, 30mmol) and urea (18g, 300mmol) be blended in the round-bottomed flask of a 100mL, 160 ℃ of following heated overnight, cool to 100 ℃, add 150mL water, stir after 30 minutes, filter, collecting precipitation obtains described compound 1
φ(4.5g, 25.6mmol), productive rate 85%.The structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 11.21 (s, 1H ,-NH), 11.05 (s, 1H ,-NH), 7.69 (s, 1H ,-phH), 7.47 (d, 1H, J=7.2Hz ,-phH), 7.08 (d, 1H, J=7.2Hz ,-phH), 2.32 (s, 3H ,-CH
3);
13CNMR (DMSO-d
6, 100MHz) δ: 162.8,150.3,138.7,135.9,131.5,126.5,115.3,114.2,20.2; ESI-MS m/z (%): 176.0 (M, 100%).As from the foregoing, this compound structure is correct, is described compound 1
φ
Described base is T
NaThe peptide nucleic acid(PNA) of (R is H) is a compound 5
Na, be to be prepared as follows and to get:
With midbody compound 2
Na(130mg, 0.5mmol) and HBTU (170mg 0.5mmol) is mixed in 1 milliliter N, in the dinethylformamide (DMF), adds and sec.-propyl ethylamine (DIEA, 0.5 mmol).Stir after 30 minutes, add compound 3
Na(120mg, 0.5mmol) 1 milliliter of DMF solution, after the stirring at room 3 hours, pour in 20 ml waters, collecting precipitation is after ethyl acetate washing, extraction, the organic layer anhydrous magnesium sulfate drying, the oily matter of removing behind the organic solvent is crossed post with silica gel, and using by volume ratio is the mixed solution drip washing that 10: 1 methylene dichloride and ethyl acetate are formed, and obtains product compound 4
Na(200mg, 0.41mmol), productive rate 80%.With compound 4
NaBe dissolved in volume ratio and be in 1: 15 milliliters of the mixed solvents of forming by methylene dichloride and ethanol, add the sodium hydroxide of 1 mmole, stirring at room 2 hours, the back is with the neutralization of 1N hydrochloric acid, and the pH value of transferring solution is removed organic solvent and is obtained compound 5 to 3-5
Na, productive rate is 100%.The structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 13.04 (s, 1H ,-OH), 11.67 (s, 1H ,-NH), 8.71 (s, 1H ,-naph-H), 8.15 (d, 1H, J=8.4Hz ,-naph-H), 7.95 (d, 1H, J=8.4Hz,-naph-H), 7.63 (t, 1H, J=8.0Hz ,-naph-H), 7.59 (s, 1H ,-naph-H), 7.48 (t, 1H, J=8.0Hz ,-naph-H), 4.90 (s, 2H ,-CH
2), 3.0 (d, 2H, J=5.6Hz ,-CH
2), 2.5 (m, 3H ,-CH
2), 2.1 (s, 1H ,-CH
2), 1.37 (s, 9H ,-Boc-H);
13C NMR (DMSO-d
6, 100MHz) δ: 169.4,161.7,149.8,136.4,134.9,131.2,129.6,129.5,128.6,126.8,125.1,114.2,110.4,80.5,54.2,52.8,49.8,41.4,28.6,20.2; ESI-MSm/z (%): 469.2 (M-H
-, 100%).As from the foregoing, this compound structure is correct, is the uracil of naphtho-shown in formula III peptide nucleic acid monomer (compound 5
Na).
Wherein, midbody compound 2
NaBe to be prepared as follows and to get:
1) under 20 ℃ heating condition, with naphtho-uridylic (4.0g, 18.8mmol, compound 1
Na) be dissolved among 100 milliliters the DMSO, (3.76g, 94.0mmol), under 20 ℃ heating condition, stirring reaction 1 hour obtains reaction soln (A) to add NaOH.2) (2.512g 18.8mmol) is dissolved among 4 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under 20 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 1 hour.Reaction solution is poured in 200 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 200 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 1.2 gram (5.7mmol) compounds 1, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.91 gram (3.4mmol) compound 2
Na, productive rate 18%.The nuclear-magnetism structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 13.04 (s, 1H ,-OH), 11.67 (s, 1H ,-NH), 8.71 (s, 1H ,-naph-H), 8.15 (d, 1H, J=8.4Hz ,-naph-H), 7.95 (d, 1H, J=8.4Hz,-naph-H), 7.63 (t, 1H, J=8.0Hz ,-naph-H), 7.59 (s, 1H ,-naph-H), 7.48 (t, 1H, J=8.0Hz ,-naph-H), 4.90 (s, 2H ,-CH
2), 2.35 (s, 3H ,-CH
3);
13C NMR (DMSO-d
6, 100MHz) δ: 169.4,161.7,149.8,136.4,134.9,131.2,129.6,129.5,128.6,126.8,125.1,114.2,110.4,41.4; ESI-MS m/z (%): 269.1 (M-H
-, 100%).As from the foregoing, this compound structure is correct, is the intermediate (compound 2 of the peptide nucleic acid monomer of benzo uracil shown in the formula I
Na).
Wherein, used reactant compound 1 in above-mentioned preparation method's step 1)
NaBe to be prepared as follows and to get: with commercially available 2-amino-5 methyl-phenylformic acid (5.61g, 30mmol) and urea (18g, 300mmol) be blended in the round-bottomed flask of a 100mL, 160 ℃ of following heated overnight, cool to 100 ℃, add 150mL water, stir after 30 minutes, filter, collecting precipitation obtains described compound 1
Na(5.2g, 24.5mmol), productive rate 82%.The structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 11.31 (s, 1H ,-NH), 11.20 (s, 1H,-NH), 8.64 (s, 1H ,-naph-H), 8.10 (d, 1H, J=8.4Hz ,-naph-H), 7.90 (d, 1H, J=8.4Hz ,-naph-H), 7.61 (t, 1H, J=8.0Hz,-naph-H), 7.52 (s, 1H ,-naph-H), 7.47 (t, 1H, J=8.0Hz ,-naph-H);
13C NMR (DMSO-d
6, 100MHz) δ: 162.9,150.3,136.5,136.3,129.5,129.2,129.0,128.5,126.7,124.9,115.2,110.2; GCT-MS m/z (%): 212.0 (M, 100%).As from the foregoing, this compound structure is correct, is described compound 1
Na
Embodiment 12, have the peptide nucleic acid nano heterojunction 2 of electric potential gradient with the preparation of embodiment 10 preparation gained peptide nucleic acid monomers:
Preparation Pc-R
2-CONH-AAAAA-CONH-R
1-PDI-R
1-NHCO-T
NaT
φT
φ 'T
Py-8T
Py-5-NHCO-R
2-Pc peptide nucleic acid nano heterojunction 2 (wherein, base T
φIn substituent R=-CH
3, T
Na, T
Py-5And T
Py-8In substituent R be H, T
φ 'In substituent R=-OCH
3)
1) is start element with 4-toluene hydrogen amine (mbha resin),, handles 3 times that each 3 minutes is that 1: 1 DMF/DCM washes 3 times with the 2mL mol ratio respectively then, after the 2mL pyridine is washed twice, is T with base with 2mL trifluoroacetic acid (TFA) with after the methylene dichloride swelling
1Peptide nucleic acid monomer activate with dehydration catalyst and diisopropyl ethyl amine after, with mbha resin in 125 μ L N, react in the dinethylformamide (DMF), use the DMF washed twice, with capping reagent (diacetyl oxide) handle and washing after, obtain MBHA-T
NaCompound;
2) with described MBHA-T
NaCompound and base are T
φPeptide nucleic acid monomer carry out dehydration reaction, obtain MBHA-T
NaT
φCompound;
3) repeating said steps 2) 3 times, obtain MBHA-T
NaT
φT
φ 'T
Py-8T
Py-5Compound;
4) Pc is activated with dehydration catalyst and diisopropyl ethyl amine after, with described MBHA-T
NaT
φT
φ 'T
Py-8T
Py-5Compound reacts, and obtains MBHA-T
NaT
φT
φ 'T
Py-8T
Py-5-R
2-Pc compound;
5) with described MBHA-T
NaT
φT
φ 'T
Py-8T
Py-5-R
2-Pc compound and 5mL trifluoroacetic acid and 5mL TFMSA react, and use the ethyl acetate post precipitation, collecting precipitation, and obtaining unpurified skeleton symbol is HOOC-T
NaT
φT
φ 'T
Py-8T
Py-5-R
2The peptide nucleic acid(PNA) molecule A of-Pc;
With above-mentioned unpurified skeleton symbol is HOOC-T
NaT
φT
φ 'T
Py-8T
Py-5-R
2The peptide nucleic acid(PNA) molecule A of-Pc is dissolved among the 2mLDMF, is injected in the high pressure liquid chromatograph (HPLC), uses TFA/H
2O (volume ratio 0.5%) and CH
3CN/H
2The mixed solvent wash-out of O (volume ratio 0.5%) is collected elutriant, determine required product with mass spectrum (TOF-MS) after, lyophilize, the gained solid detects with HPLC and TOF-MS again, determines that its structural formula is errorless, is HOOC-T
NaT
φT
φ 'T
Py-8T
Py-5-R
2-Pc;
6) with the mbha resin be start element,, handle 3 times that each 3 minutes is that 1: 1 DMF/DCM washes 3 times with the 2mL mol ratio respectively then, after the 2mL pyridine is washed twice, is A with base with 2mL trifluoroacetic acid (TFA) with after the methylene dichloride swelling
1Peptide nucleic acid monomer activate with dehydration catalyst and diisopropyl ethyl amine after, with mbha resin in 125 μ L N, react in the dinethylformamide (DMF), use the DMF washed twice, with capping reagent (diacetyl oxide) handle and washing after, obtain MBHA-A
1Compound;
7) with described MBHA-A
1Compound and base are that the peptide nucleic acid monomer of A2 carries out dehydration reaction, obtain MBHA-A
1A
2Compound;
8) repeating said steps 7) 3 times, obtain MBHA-A
1A
2A
nCompound;
9) Pc is activated with dehydration catalyst and diisopropyl ethyl amine after, with described MBHA-A
1A
2A
nCompound reacts, and obtains MBHA-A
1A
2A
n-R
2-Pc compound;
10) with described MBHA-A
1A
2A
n-Pc compound and trifluoroacetic acid and TFMSA react, and use the ethyl acetate post precipitation, collecting precipitation, and obtaining skeleton symbol is HOOC-A
1A
2A
n-R
2The peptide nucleic acid(PNA) molecule B of-Pc;
Above-mentioned unpurified peptide nucleic acid nano heterojunction molecule B is dissolved among the 2mL DMF, is injected in the high pressure liquid chromatograph (HPLC), use TFA/H
2O (volume ratio 0.5%) and CH
3CN/H
2The mixed solvent wash-out of O (volume ratio 0.5%) is collected elutriant, determine required product with mass spectrum (TOF-MS) after, lyophilize, the solid that obtains detects with HPLC and TOF-MS again, determines that its structural formula is errorless, is HOOC-A
1A
2A
n-R
2-Pc.
11) be HOOC-T with described skeleton symbol
NaT
φT
φ 'T
Py-8T
Py-5-R
2The peptide nucleic acid(PNA) molecule A of-Pc is dissolved among the DMF of 1mL, after the activation of dehydration catalyst and diisopropyl ethyl amine, in DMF, react 30 minutes with 1mL PDI after, adding is HOOC-A with dehydration catalyst and diisopropyl ethyl amine activatory skeleton symbol again
1A
2A
n-R
2The peptide nucleic acid(PNA) molecule B reaction of-Pc is after 30 minutes, and HPLC separates, and obtains described Pc-R
2-CONH-AAAAA-CONH-R
1-PDI-R
1-NHCO-T
NaT
φT
φ 'T
Py-8T
Py-5-NHCO-R
2-Pc has the peptide nucleic acid(PNA) molecule of PDI and Pc for another covalent coupling;
12) being dissolved in by 50 μ L water and 50 μ L concentration by the peptide nucleic acid(PNA) molecule of PDI and Pc the covalent coupling that obtains in the described step 11) is in the mixed solution formed of the NaCl aqueous solution of 200mM/L, place 37 ℃ incubator to cultivate 2 hours, obtain the described PNA of formula I and be-NHCO-Tn-NHCO-R
2The peptide nucleic acid nano heterojunction 2 of-Pc.
In described step 1)-step 11), described reaction is reaction with same mole, and in the step 1), described base is T as described
1The mol ratio of peptide nucleic acid monomer, dehydration catalyst, diisopropyl ethyl amine and 4-toluene hydrogen amine (mbha resin) be 1: 1: 1: 1.In each reactions steps, the consumption of organic solvent gets final product with complete solubilizing reaction thing.Described dehydration catalyst is benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate.
This peptide nucleic acid nano heterojunction 2 can prepare biological organic photovoltaic battery according to ordinary method, and its preparation method is as follows:
Handling on the clean ito glass surface, after spin coating one layer thickness is the PSS/PEDOT (the poly-p styrene sulfonic acid of poly-dioxoethyl thiophene) of 40nm, 150 ℃ of dryings after 0.5 hour, be spin-coated on this PSS/PEDOT layer in the mixture with described peptide nucleic acid nano heterojunction 2 and oil of mirbane composition, obtain the active coating (thickness is 100nm) of biological organic photovoltaic battery, after 1 hour, is 5 * 10 in vacuum tightness in 100 ℃ of dryings
-5Under the condition of Pa, evaporation one layer thickness is the metal aluminium electrode of 150nm, obtains described biological organic photovoltaic battery.
Described base is T
NaThe peptide nucleic acid(PNA) of (R is H) is to get according to the method preparation that embodiment 11 provides.
Described base is T
φ(R=-CH
3) peptide nucleic acid(PNA) be the method preparation that provides according to embodiment 11 and getting.
Described base is T
Py-8The peptide nucleic acid(PNA) of (R is H) is to get according to the method preparation that embodiment 11 provides.
Described base is T
φ '(R=-CH
3) peptide nucleic acid(PNA) be to be prepared as follows and to get:
With compound 2
φ '(140mg, 0.5mmol) and HBTU (170mg 0.5mmol) is mixed in 1 milliliter N, in the dinethylformamide (DMF), adds N, and (DIEA 0.5mmol) stirs after 30 minutes the N-diisopropyl ethyl amine, adds compound 3
φ '(120mg, 0.5mmol) 1 milliliter of DMF solution, after the stirring at room 3 hours, pour in 20 ml waters, collecting precipitation is after ethyl acetate washing, extraction, the organic layer anhydrous magnesium sulfate drying, the oily matter of removing behind the organic solvent is crossed post with silica gel, and using by volume ratio is the mixed solution drip washing that 10: 1 methylene dichloride and ethyl acetate are formed, and obtains product compound 4
φ '(210mg, 0.42mmol), productive rate 81%.With compound 4
φ 'Being dissolved in by volume ratio is in 5 milliliters of the mixed solvents formed of 1: 1 methylene dichloride and ethanol, adds the sodium hydroxide of 1 mmole, stirring at room 2 hours, and the back is with the neutralization of 1N hydrochloric acid, and the pH value of transferring solution is removed organic solvent and is obtained compound 5 to 3-5
φ ', productive rate is 100%.This compound 5
φ 'Nuclear-magnetism to detect data as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 12.99 (s, 1H ,-OH), 11.49 (s, 1H ,-NH), 7.29 (s, 1H ,-ph-H), 6.71 (s, 1H ,-ph-H), 4.55 (s, 2H ,-CH
2), 3.85 (s, 3H ,-CH
3), 3.80 (s, 3H ,-CH
3), 3.0 (d, 2H, J=5.6Hz ,-CH
2), 2.5 (m, 3H ,-CH
2), 2.1 (s, 1H ,-CH
2), 1.37 (s, 9H ,-Boc-H);
13CNMR (DMSO-d
6.100MHz) δ: 169.3,169.1,160.7,155.4,150.2,137.7,136.7,132.8,127.6,125.3,114.2,80.5,56.2,54.8,54.2,52.8,49.8,42.3,28.6; ESI-MS m/z (%): 479.0 (M-H
-, 100%).As from the foregoing, this compound structure is correct, is the uracil of benzo shown in formula III peptide nucleic acid monomer (compound 5
φ ').
Wherein, described compound 2
φ 'Be to be prepared as follows and to get:
1) under the heating condition of 20C, with dimethoxy benzo uridylic (4g, 18mmol, compound 1
φ ') be dissolved among 90 milliliters the DMSO, (3.6g, 90mmol), under the heating condition of 20C, stirring reaction obtained reaction soln (A) after 1 hour to add NaOH.2) (2.5g 18mmol) is dissolved among 5 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under the heating condition of 20C, reaction soln B is joined among the reaction soln A, after adding, continue to stir 12 hours.Reaction solution is poured in 150 milliliters of ethyl acetate, collected the precipitation obtain, precipitation is dissolved in 100 ml waters, the pH value of transferring solution with 6N hydrochloric acid is to pH=7, filters to obtain 1.6 and restrain (7.2mmol) compounds 1
φ ', transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.81 gram (2.9mmol) product compound 2
φ ', productive rate 16%.The nuclear-magnetism structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 12.94 (s, 1H ,-OH), 11.36 (s, 1H ,-NH), 7.29 (s, 1H ,-ph-H), 6.71 (s, 1H ,-ph-H), 4.53 (s, 2H ,-CH
2), 3.85 (s, 3H ,-CH
3), 3.80 (s, 3H ,-CH
3);
13C NMR (DMSO-d
6, 100MHz) δ: 169.4,161.6,149.8,137.2,136.4,132.1,126.8,115.3,113.2,56.2,54.3,41.3; EI-MS m/z (%): 280.1 (M, 100%).As from the foregoing, this compound structure is correct, is the intermediate (compound 2 of the peptide nucleic acid monomer of benzo uracil shown in the formula I
φ ').Wherein, used reactant compound 1 in the described step 1)
φ 'Be to be prepared as follows and to get: with commercially available 2-amino-4,5-dimethoxy-phenylformic acid (5.92g, 30mmol) and urea (18g, 300mmol) be blended in the round-bottomed flask of a 100mL, 160 ℃ of following heated overnight cool to 100 ℃, add 150mL water, stir after 30 minutes, filter, collecting precipitation obtains described compound 1
φ '(5.8g, 26.1mmol), productive rate 87%.The structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 11.36 (s, 1H ,-NH), 11.21 (s, 1H ,-NH), 7.29 (s, 1H ,-ph-H), 6.71 (s, 1H ,-ph-H), 3.85 (s, 3H ,-CH
3), 3.80 (s, 3H ,-CH
3);
13C NMR (DMSO-d
6, 100MHz) δ: 161.6,149.8,137.2,136.4,132.1,126.8,115.3,113.2,56.2,54.3; GCT-MS m/z (%): 222.2 (M, 100%).As from the foregoing, this compound structure is correct, is described compound 1
φ '
Described base is T
Py-5The peptide nucleic acid(PNA) of (R is H) is a compound 11, is to be prepared as follows and to get:
1) with intermediate (compound 6) (111mg, 0.5mmol), HBTU (224.4mg 0.66mmol) is mixed in 3 milliliters N, in the dinethylformamide (DMF), adds N, the N-diisopropyl ethyl amine (DIEA, 0.66mmol).Stir after 40 minutes, add compound 7 (144mg, 3 milliliters of DMF solution 0.66mmol), after the stirring at room 5 hours, pour in 30 ml waters, collecting precipitation is after ethyl acetate washing, extraction, the organic layer anhydrous magnesium sulfate drying, the oily matter of removing behind the organic solvent is crossed post with silica gel, and using by volume ratio is the mixed solution drip washing that 10: 1 methylene dichloride and ethyl acetate are formed, and obtains product compound 10 (188mg, 0.42mmol), productive rate 84%.2) product compound 10 being dissolved in volume ratio is in 1: 16 milliliters of the mixed solvents of being made up of methylene dichloride and ethanol, the sodium hydroxide that adds 1.2 mmoles, stirring at room 3 hours, the back neutralizes with 1N hydrochloric acid, the pH value of regulator solution is to 3-5, remove organic solvent and obtain compound 11, productive rate is 100%.It is as follows that the nuclear-magnetism of this compound 11 detects data:
1H-NMR (400MHz, DMSO-d
6) δ: 13.08 (s, 1H ,-OH), 11.49 (s, 1H ,-NH), 8.71 (d, 1H, J=8.0Hz ,-pyH), 8.28 (d, 1H, J=8.0Hz ,-pyH), 7.28 (q, 1H, J=4.8 and 6.8Hz ,-pyH), 6.5 (s, 1H ,-NH), 4.55 (s, 2H ,-CH
2), 3.85 (s, 2H ,-CH
2), 3.0 (m, 2H ,-CH
2), 2.5 (m, 2H ,-CH
2), 1.37 (s, 9H ,-Boc-H);
13C NMR (DMSO-d
6, 100MHz) δ: 169.3,168.5,160.7,154.4,152.2,148.7,138.7,135.2,117.6,115.3,80.5,54.2,52.8,49.8,42.3,28.6; ESI-MSm/z (%): 420.0 (M-H
-, 100%).As from the foregoing, this compound structure is correct, is the uracil of benzo shown in formula III peptide nucleic acid monomer (compound 11).
Wherein, described midbody compound 6 is to be prepared as follows and to get:
1) under 20 ℃ heating condition, pyridino-uracil (4g, 24.5mmol, compound 5) is dissolved among 100 milliliters the DMSO, (9.0g, 227.1mmol), under 20 ℃ heating condition, stirring reaction 3 hours obtains reaction soln (A) to add NaOH.2) (3.48g 24.9mmol) is dissolved among 3 milliliters of DMSO, obtains reaction soln (B) with bromoacetic acid.Under 20 ℃ heating condition, reaction soln B is joined among the reaction soln A, after adding, continue to stir 10 hours.Reaction solution is poured in 130 milliliters of ethyl acetate, the precipitation that collection obtains, precipitation is dissolved in 130 ml waters, transfer the pH value of solution to pH=7 with 6N hydrochloric acid, filtration obtains 1.5 gram (9.2mmol) compounds 1, transfer pH value of filtrate to 2 with 6N hydrochloric acid, filter and obtain 0.81 gram (3.7mmol) product compound 6, productive rate 15%.It is as follows that the nuclear-magnetism of this product detects data:
1H-NMR (400MHz, DMSO-d
6) δ: 13.04 (s, 1H ,-NH), 11.48 (s, 1H ,-NH), 8.60 (d, 1H, J=8.0Hz ,-pyH), 8.30 (d, 1H, J=8.0Hz ,-pyH), 7.31 (q, 1H, J=4.8 and 6.8Hz ,-pyH), 4.53 (s, 2H ,-CH
2), 3.30 (s, 3H ,-CH
3);
13C NMR (DMSO-d
6, 100MHz) δ: 169.4,161.9,154.8,151.3,149.4,135.7,118.5,114.2,41.2; GCT-MS m/z (%): 221.0 (M, 100%).As from the foregoing, this compound structure is correct, is the intermediate (compound 6) of benzo uracil peptide nucleic acid monomer.Wherein, used reactant compound 5 pyridino-uracils are to be prepared as follows and to get in the aforesaid method step 1):
With commercially available 2-amino-3-carboxyl-pyridine (4.14g, 30mmol, compound 4) and urea (18g 300mmol) is blended in the round-bottomed flask of a 100mL, 160 ℃ of following heated overnight, cool to 100 ℃, add 50mL water, stir after 30 minutes, filter, collecting precipitation obtain compound 5 (3.5g, 21.5mmol), productive rate 71%.The structural characterization data of this product are as follows:
1H-NMR (400MHz, DMSO-d
6) δ: 11.64 (s, 1H ,-NH), 11.48 (s, 1H ,-NH), 8.60 (d, 1H, J=8.0Hz ,-pyH), 8.30 (d, 1H, J=8.0Hz ,-pyH), 7.31 (q, 1H, J=4.8 and 6.8Hz ,-pyH), 3.30 (s, 3H ,-CH
3);
13C NMR (DMSO-d
6, 100MHz) δ: 162.2,154.8,151.3,150.4,135.7,126.5,110.2,20.2; GCT-MS m/z (%): 163.0 (M, 100%).As from the foregoing, this compound structure is correct, is compound 5.
Claims (12)
1. formula I or the described compound of formula II general structure,
(formula I)
(formula II)
In described formula I and the formula II general structure, R is-F ,-Cl ,-Br ,-I ,-H ,-CH
3,-CH
2CH
3Or-CH
2CH
2CH
3
2. a method for preparing the described compound of claim 1 Chinese style I comprises the steps:
1) analog derivative of pyridino-uracil shown in the formula III is reacted with sodium hydroxide in organic solvent, reaction finishes and obtains reaction soln A;
(formula III)
In the described formula III, R is-F ,-C1 ,-Br ,-I ,-H ,-CH
3,-CH
2CH
3Or-CH
2CH
2CH
3
2) bromoacetic acid is dissolved in the organic solvent, obtains reaction soln B, described reaction soln B and described reaction soln A are reacted, obtain the described compound of claim 1 Chinese style I.
3. method according to claim 2 is characterized in that: in the described step 1), described organic solvent is selected from dimethyl sulfoxide (DMSO) and N, at least a in the dinethylformamide, preferred dimethyl sulfoxide (DMSO); The amount ratio of pyridino-uracil analog derivative, sodium hydroxide and described organic solvent shown in the described formula III is 1mmol: 2-10mmol: 2-10ml;
Described step 2) in, described organic solvent is selected from dimethyl sulfoxide (DMSO) and N, at least a in the dinethylformamide, preferred dimethyl sulfoxide (DMSO); The amount ratio of described bromoacetic acid and described organic solvent is 1-1.5mmol: 0.05-0.3ml; In the described reactions steps, temperature is 20-80 ℃, and preferred 20-70 ℃, the time is 5-15 hour, preferred 8-10 hour.
4. according to claim 2 or 3 described methods, it is characterized in that: in described step 2) reaction finish after, reaction system is carried out following purification process: with reaction system and ethyl acetate mixing, the precipitation that collection obtains, described precipitation is soluble in water, regulate pH value to 2, obtain the described compound of claim 1 Chinese style I behind the purifying.
5. a method for preparing the described compound of claim 1 Chinese style II comprises the steps:
1) pyridino-uracil analog derivative shown in the formula IV is reacted with sodium hydroxide in organic solvent, reaction finishes and obtains reaction soln A;
(formula IV)
Among the described formula IV, R is-F ,-Cl ,-Br ,-I ,-H ,-CH
3,-CH
2CH
3Or-CH
2CH
2CH
3
2) bromoacetic acid is dissolved in the organic solvent, obtains reaction soln B, described reaction soln B and described reaction soln A are reacted, obtain the described compound of claim 1 Chinese style II.
6. method according to claim 5 is characterized in that: in the described step 1), described organic solvent is selected from dimethyl sulfoxide (DMSO) and N, at least a in the dinethylformamide, preferred dimethyl sulfoxide (DMSO); The amount ratio of pyridino-uracil analog derivative, sodium hydroxide and described organic solvent shown in the described formula IV is 1mmol: 2-10mmol: 2-10ml; Temperature is 20-80 ℃, and preferred 20-70 ℃, the time is 10-300 minute, preferred 100-200 minute;
Described step 2) in, described organic solvent is selected from dimethyl sulfoxide (DMSO) and N, at least a in the dinethylformamide, preferred dimethyl sulfoxide (DMSO); The amount ratio of described bromoacetic acid and described organic solvent is 1-1.5mmol: 0.1-1.0ml; In the described reactions steps, temperature is 20-80 ℃, and preferred 20-70 ℃, the time is 5-15 hour, preferred 8-10 hour.
7. according to claim 5 or 6 described methods, it is characterized in that: in described step 2) reaction finish after, reaction system is carried out following purification process: with reaction system and ethyl acetate mixing, the precipitation that collection obtains, described precipitation is soluble in water, regulate pH value to 2, obtain the described compound of claim 1 Chinese style II behind the purifying.
8. peptide nucleic acid monomer compound shown in formula V or the formula VI,
(formula V)
(formula VI)
Among described formula V and the formula VI, R is-F ,-Cl ,-Br ,-H ,-I ,-CH
3,-CH
2CH
3Or-CH
2CH
2CH
3
9. a method for preparing the described peptide nucleic acid monomer compound of claim 8 comprises the steps:
With the described compound of claim 1 and benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate in organic solvent a with N, after the N-diisopropylethylamine at room temperature reacts 10-30 minute, add N-tert.-butoxy-carbonyl-1 again, the organic solution of 2-diaminoethanes is at room temperature reacted after 60-240 minute and is obtained product a, described product a at room temperature reacted 30-120 minute with sodium hydroxide in organic liquid mixture after, regulate the pH value to 3-5, obtain the described peptide nucleic acid monomer compound of claim 6; The organic solution of described N-tert.-butoxy-carbonyl-1 is described N-tert.-butoxy-carbonyl-1 is dissolved among the organic solvent b and gets.
10. method according to claim 9 is characterized in that: described organic solvent a and organic solvent b all are selected from N, at least a in dinethylformamide and the dimethyl sulfoxide (DMSO), preferred N, dinethylformamide; Described organic liquid mixture is to be that 1: 1 methylene dichloride mixes with ethanol and gets by volume ratio;
The described compound of described claim 1, benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate, organic solvent a, N, N-diisopropylethylamine, N-tert.-butoxy-carbonyl-1,2-diaminoethanes, organic solvent b: the amount ratio of sodium hydroxide is 1mmol: 1-1.32mmol: 0.5-6m1: 1-1.32mmol: 1-1.32mmol: 0.5-6ml: 1-3mmol, preferred 1mmol: 1mmol: 2ml: 1mmol: 1mmol: 2ml: 2mmol or 1mmol: 1.32mmol: 6ml: 1.32mmol: 1.32mmol: 6ml: 2.4mmol.
11. the described peptide nucleic acid monomer compound of claim 8 has application in the nucleic acid bionic material of electric potential gradient in preparation.
12. with the described peptide nucleic acid monomer compound of claim 8 is the peptide nucleic acid(PNA) that monomer prepares.
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