CN1107676C - Cationic imide as polypeptide condensing agent and its synthesis - Google Patents

Cationic imide as polypeptide condensing agent and its synthesis Download PDF

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CN1107676C
CN1107676C CN99113545A CN99113545A CN1107676C CN 1107676 C CN1107676 C CN 1107676C CN 99113545 A CN99113545 A CN 99113545A CN 99113545 A CN99113545 A CN 99113545A CN 1107676 C CN1107676 C CN 1107676C
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condensing agent
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CN1267672A (en
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李鹏
徐杰诚
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to a cationic imide polypeptide condensing agent and a synthesis method thereof. The molecule formula is disclosed in the right formula. Firstly, corresponding imide reacts with a chloridizing agent at-30 to 0 DEG C; then, after an organic solvent of a stabilizing agent is dripped at-10 to 50 DEG C, the imide further reacts with an activation component for obtaining the condensing agent. The condensing agent is superior to the developed urea cationic condensing agent and the developed phosphorus cationic condensing agent at present at the aspects of reactivity and the racemization degree of a product when the polypeptide condensing agent is used for synthesizing peptide. The polypeptide condensing agent can be used for synthesizing a liquid phase and a solid phase. Moreover, the present invention has the advantages of simple and convenient synthesis, low price of raw material, easy acquirement of the raw material, stability at room temperature, convenient operation, etc., and can be widely applied to the synthesis of polypeptide imide, ester and activation ester.

Description

Cationic imide as polypeptide condensing agent and synthetic
The present invention relates to a peptide species condensing agent and a synthetic method thereof, i.e. cationic imide as polypeptide condensing agent and synthetic.
The method of peptide synthetic most convenient is that intermediate directly reacts without separation under the condensing agent effect with carboxy moiety and amino partially mixed, so just need not prepare mixed acid anhydride and Acibenzolar in advance.Particularly in solid phase synthesis, what real at present energy was practical still is the condensing agent method.
In the condensing agent method, generally use so far, most widely used is dicyclohexylcarbodiimide (DCCl) method.It is synthetic that DCCl is that Sheehan and Hess at first are used for peptide in nineteen fifty-five, can produce a lot of side reactions but DCCl makes condensing agent, as forming N-acylurea by-product in the reaction process, racemization takes place.As D.R.Detar, R.Silverstein, F.F.Rogers, J.Am.Chem.Soc., 1966,88,1024. and D.R.Detar, R.Silverstein, J.Am.Chem.Soc., 1966,88,1020. when the DCCl of middle report activation Asn and Gln, can also cause that ω-amide group dehydration forms the side reaction of cyano group.Another shortcoming of DCCl method is the N that reaction generates, and N '-dicyclohexylurea (DCU) DCU solubleness in most of organic solvents is very little, is mixed in sometimes in the product and is difficult to eliminate.People improve on the structure of DCCl for this reason, some water miscible carbodiimides have been developed, as N-cyclohexyl-N '-(4-diethylamino cyclohexyl)-phosphinylidyne diimine, N-cyclohexyl-N '-[2-(4-methylmorpholine base)-ethyl] phosphinylidyne diimine tosilate and N-ethyl-N '-[3-(N, the N-dimethylamino) propyl group]-the phosphinylidyne diimine replaces DCCl, but all is not widely used.
Phosphorus positive ion of developing in recent years and carbonium ion type condensing agent have preferable performance.From 1975, people such as Castro synthesized since the bop reagent, were that the phosphorus positive ion type and the carbonium ion type reagent of Acibenzolar develops rapidly with the I-hydroxybenzotriazole, as Coste, J., Le-Nguyen, D.And Castro, B., Tetrahedron Lett., reported PyBOP in 1990,31,205 documents such as grade, HBTU, HBPyU, HBPipU, HBMDU, HBMTU etc. are the condensing agent of Acibenzolar with HOBt.
Figure C9911354500071
BOP PyBOP
HBTU HBPyU HBPipU
HBMDU HBMTU HOAt
But in this class reagent, except that BOP and HBTU be employed in synthetic, remaining reagent all was not commonly used.And also there are some shortcomings in BOP and HBTU, as in document Rowell, R.M., Appl.Biochem.Biotechnol, 1984,9,447; Oustrin, M.L., Moisand, C., Cros, M.L.and Bonnefoux, J., Ann.Pharm.Fr., 1972,30,685; Moisand, A., Moisand, C.and Pitet, G., Ann.Pharm.Fr. points out in 1970,28,575 in preparation and when using BOP, can run into the HMPA that carcinogenic toxicity is arranged.HBTU also has same problem, and in preparation and use, the tetramethyl-urea element that runs into also is to have cytotoxic material.Producing racemization also is a shortcoming of this class reagent.In Yang Shi racemization test, find that condensing agent BOP has 39.8% racemization product, and condensing agent HBTU also have 25.4% racemization product (Chen, S.Q.and Xu, J.C., Tetrahedron Lett., 1992,33,647-650).At document Galpin, I.J., Gordon, P.F., Ramage, R.and Thorpe, W.D., Tetrahedron, people such as Galpin is reported in BOP condensation Z-Gly-Ala-OH and H-Leu-OCH in 1976,32,2417 229% racemization is arranged in the process of Ph.At document Steinauer, R., Chen, F.M.F.and Benoiton, N.L., Int.J.PeptideProtein Res., people such as Steinauer thinks that bop reagent is owing to the racemization degree of itself causes being not suitable for property in the fragment condensation of peptide in 1989,34,295.
In recent years, people have developed some phosphorus positive ion type and carbonium ion type condensing agents based on 7-azepine-I-hydroxybenzotriazole HOAt again, as at document Albericio, F., Cases, M., Alsina, J., Triolo, S.A., Carpino, L.A.and Kates, S.A., Tetrahedron Lett., 1997,38,4853; Carpino, L.A., El-Faham, A., Minor, C.A.and Albericio, F., J.Chem.Soc.Chem.Commun., 1994,201; Angell, Y.M., Thomas, T.L.and Rich, D.H., Peptides:Chemistry, structure and Biology, Pravin, T.P., Kaumaya andHodges, R.S. (Eds), Mayflower Scientific Ltd., 1996, p88; Deng in the report AOP, PyAOP, HATU, HAPipU, HAPyU, HAMDU, reagent such as HAMTU.Though this type of reagent has higher activity and less racemization based on the condensing agent of HOBt accordingly, preparation is difficulty, and less stable, price are also relatively more expensive, therefore also are not widely used.Carpino, L.A., J.Am.Chem.Soc, 1993,115,4397; Raman, P., Stokes, S.S., Angll, Y.M., Flentke, G.R.and Rich, D.H., J.Org.Chem., 1998,63,5734; Angll, Y.M., Thomas, T.L., Flentke, G.R.and Rich, D.H., Am.Chem.Soc., in 1995,117,7279 mainly be with HOAt as additive and DIPCDI, condensing agents such as DCC are united use.
Document Carpino, L.A., El-Faham, A., Minor, C.A.and Albericio, F., J.Chem.Soc.Chem.Commun. has proved that carbonium ion type condensing agent compares with corresponding phosphorus positive ion type condensing agent and have higher activity in 1994,201.Carbonium ion type condensing agent based on HOBt or HOAt is urea positive ion type at present, and its general structure is as follows: A=PF 6 -, BF 4 -X=CH, N; R 1, R 2=alkyl
Because two existence that contain the nitrogen-atoms of lone-pair electron in carbonium ion ortho position, this carbonium ion had great stabilization, and the main nitrogen positive ion of molecule form exists, but because the reactive center that carbonium ion is this type of condensing agent when participating in forming the reaction of amido linkage, so people are accustomed to claiming that this type of condensing agent is a carbonium ion type condensing agent.
Because the resonance structure of two equivalences that two amino substituting groups cause causes the stable of this compounds, also can be described as the reactive behavior that has weakened them.At document Wijkmans, J.C.H.M., Blok, F.A.A., van der Marel, G.A., vanBoom, J.H.and Bloemhoff, W., Tetrahedron Lett., 1995,36,4643; Wijkmans, J.C.H.M., Kruijtzer, A.W., van der Marel, G.A., vanBoom, J.H.and Bloemhoff, W., Recl.Trav.Chim.Pays-Bas, 1994, reported in 113,394 at Acibenzolar and partly introduced trifluoromethyl, electron-withdrawing substituents such as nitro improve the activity of condensing agent.We sound out one in the urea positive ion condensing agent amino activity with alkyl, aryl even hydrogen replacement further raising condensing agent, for this reason, have designed and synthesized the novel cationic imide type condensing agent of a class.
Purpose of the present invention just provides the novel cationic imide as polypeptide condensing agent of a class, and its general molecular formula is: R wherein 1, R 2, R 3=H, C nH 2n+1, phenyl, substituted-phenyl, described n=1-5, described substituting group are F or CF 3, R wherein 5, R 6=CF 3, NO 2, X=CH, N;
Figure C9911354500093
R wherein 7, R 8=H, C nH 2n+1, COOEt, COOCH 3, CF 3, NO 2, n as previously mentioned;
Figure C9911354500094
R wherein 9, R 10=NO 2, CF 3
Figure C9911354500095
Perhaps R 1And R 3Form propylidene, R 2=methyl,
Figure C9911354500096
Figure C9911354500097
Perhaps R 1And R 3Form butylidene, R 2=phenyl, Perhaps R 1And R 3Form propenylidene, R 2=methyl, Perhaps R 1And R 3Form crotonylidene, R 2=methyl, Perhaps R 1And R 3Form the crotonylidene that dimethyl replaces, R 2=C 2H 5,
Figure C99113545000911
Perhaps R 1And R 3Form pentylidene, R 2=ethyl, Perhaps R 1And R 2Form butylidene, R 3=phenyl, Perhaps R 1And R 2Form butylidene, R 3=methyl, Perhaps R 1And R 2Form butylidene, R 3=H, Perhaps R 1And R 2Form pentylidene, R 3=CH 2Cl,
Figure C9911354500103
Perhaps R 1And R 2Form hexylidene,
Figure C9911354500104
Perhaps R 1, R 2=methyl, R 3=H,
Figure C9911354500105
Perhaps R 1, R 2=phenyl, R 3=CH 3,
Figure C9911354500106
Perhaps R 1, R 2=CH 3, A=SbCl 6, SbF 6, CF 3SO 3, PF 6, BPh 4, BF 4
The present invention also provides the synthetic method of this type of condensing agent, promptly at first descend and the chlorination reagent reaction at-30 ℃-0 ℃ by corresponding amide, then-10C-50 ℃ drip the organic solvent reaction of stablizer down after, further obtain corresponding condensing agent again with the activating component reaction, reaction formula is as follows:
Figure C9911354500108
R wherein 1, R 2, R 3, R 4, A as previously mentioned.Chlorination reagent is: Cl 3COCOOCCl 3, POCl 3, SOCl 2, ClCOCl, ClCOCOCl; Stablizer is: SbCl 5, AgSbF 6, KPF 6, NaBPh 4, AgBF 4, CF 3SO 3Na; Organic solvent is a polar aprotic solvent; Activating component is KR 4Or HR 4+ organic bases, wherein R 4For
Figure C9911354500109
R wherein 5, R 6=CF 3, NO 2, X=CH, N;
Figure C99113545001010
R wherein 7, R 8=H, CnH 2n+1, COOEt, COOCH 3, CF 3, NO 2
Figure C99113545001011
R wherein 9, R 10=NO 2, CF 3
Figure C99113545001012
Figure C9911354500111
Organic bases is amines such as triethylamine, diisopropyl ethyl amine, pyridine, N-methylmorpholine, N-Methylimidazole.
Novel cationic imide as polypeptide condensing agent provided by the present invention still all is far superior to urea positive ion and the phosphorus positive ion type condensing agent developed at present no matter aspect reactive behavior aspect the racemization degree of product when being used for peptide synthetic.Can be used for that liquid phase is synthetic also to be used for solid phase synthesis.This class condensing agent also has synthetic easyly in addition, and plurality of advantages such as raw material is cheap and easy to get, and is stable under the room temperature, easy to use is that novel reactivity worth of a class and application performance are all very good, is worth the condensing agent of further research and development and widespread use.
Following examples help to understand the present invention, but are not limited to content of the present invention:
Embodiment 1
Under 0 ℃, to N-Methyl pyrrolidone (0.96ml, 10ml CH 10mmol) 2Cl 2Drip triphosgene (0.989g, 5ml CH 3.333mmol) in the solution 2Cl 2Solution behind the room temperature reaction, is cooled to-20 ℃ and drips SbCl 5(1.22ml, 10ml CHCl 9.524mmol) 3Solution, low-temp reaction 1-3 hour, filter, get intermediate.
With intermediate (3.9g, 8.605mmol) be dissolved in the dry acetonitrile of 30ml, stir and be cooled to-30 ℃, add I-hydroxybenzotriazole sylvite (1.49g, 8.605mmol), behind the low-temp reaction, remove cryostat, room temperature reaction 2-4 hour, filter, filtrate is concentrated into the crystalloid solid and separates out, and product is yellow crystal shape solid BDMP, and total yield is 80%. Fusing point: 165-166 ℃ (dec.); 1H NMR (300MHz, [D 6] acetone, 25 ℃, TMS): δ=7.34-7.95 (m, 4H, aryl), 3.48 (t, 3J (H, H)=7Hz, 2H, α-CH 2), 2.83 (s, 3H, CH 3), 2.39 (t, 3J (H, H)=8Hz, 2H, γ-CH 2), 1.98-2.09 (m, 2H, β-CH 2); IR (KBr): ν=1655,1496,1479,1445,1165,1066,763,640cm -1FABMS:217[M-SbCl 6 -]; Ultimate analysis: theoretical value (C 5H 9Cl 7NSb): C23.94, H2.36, N10.15;
Measured value C23.83, H2.13, N10.24.
Embodiment 2
At first with N, dinethylformamide and triphosgene or POCl 3Effect obtains-the chlorion salt of cationic imide, and the chloroformic solution that directly drips antimony pentachloride again in reaction system promptly obtains the chlordene antimonic salt MCMI of cationic imide.Then, MCMI obtains product benzotriazole-1-oxygen base-N with the I-hydroxybenzotriazole sylvite reaction of equivalent again, and N-dimethyl methyl cationic imide hexa chloro-antimonate (BOMI), total yield are 76%. Fusing point: 152-153 ℃ (dec.); 1H-NMR (CD 3COCD 3): δ 7.99 (1H, s α-H), 7.95-7.45 (4H, m, aryl), 2.97 (3H, s, CH 3), 2.81 (3H, s, CH 3). ultimate analysis (C 9H 11Cl 6N 4OSb) theoretical value: C, 20.54; H, 2.09; N, 10.65.
Measured value: C, 20.78, H, 2.12; N, 10.63.
Embodiment 3
Synthetic route is with embodiment 1, and reaction reagent and reaction conditions and synthetic synoptic diagram are as follows, and reaction product is
Figure C9911354500122
, the reaction total yield is 80%.
Figure C9911354500123
Reaction reagent and reaction conditions: i.PhCOCl, NEt 3, CH 2Cl 2,-50 ℃ → r.t., 1hr.; Ii.a.Cl 3COCOOCCl 3, CH 2Cl 2, r.t., 1hr.; B.SbCl 5/ CHCl 3,-30 ℃, 1.5hr.; Iii.KOBt, CH 3CN ,-30 ℃ → r.t., 3hr.
The analytical data of product: fusing point: 93-94 ℃ (dec.); 1H NMR (300MHz, [D 6] acetone, 25 ℃, TMS): δ=7.34-7.97 (m, 9H, aryl), 3.57 (m, 4H, α-CH 2), 1.95 (m, 4H, β-CH 2); IR (KBr): ν=1616,1494,1467,1446,1417,1331,1309,1151,1065,752,741,705,638cm -1FABMS:293[M-SbCl 6 -]; Ultimate analysis (C 17H 17Cl 6N 4OSb): theoretical value C32.52, H2.71, N8.92;
Measured value C32.23, H2.75, N8.84.
Embodiment 4
Reactions steps is with embodiment 1, different reaction conditions and reaction reagent such as figure below, reaction product is
Figure C9911354500131
, total yield is 74%
Figure C9911354500132
The analytical data of product: fusing point: 182-183 ℃ (dec.); 1H NMR (300MHz, [D 6] acetone, 25 ℃, TMS): δ=3.46 (t, 3J (H, H)=7Hz, 2H, α-CH 2), 2.81 (s, 3H, CH 3), 2.35 (t, 3J (H, H)=8Hz, 2H, γ-CH 2), 1.97-2.07 (m, 2H, β-CH 2); 19F NMR (300MHz, [D 6] acetone, 25 ℃, CF 3COOH): δ=-76.35～-77.08 (m, 2F) ,-80.15～-80.33 (m, 2F) ,-85.84～-86.02 (m, 1F); IR (KBr): ν=1705,1530,1520,1480,1398,1034,1001,954cm -1FABMS:266[M-SbCl 6 -], 267[M-SbCl 6 -+ 1]; Ultimate analysis (C 11H 9Cl 6F 5NOSb): theoretical value C21.97, H1.50, N2.33;
Measured value C21.50, H1.34, N2.16.
Embodiment 5
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.POCl 3，CH 2Cl 2，r.t.，1hr.；
b.AgSbF 6/CHCl 3，-30℃，1.5hr.；
2, , CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is , product analytical data is: 1H NMR: δ=7.34-7.97 (m, 4H, aryl), 3.48 (t, 3J (H, H)=7Hz, 2H, α-CH 2), 2.85 (s, 3H, CH 3), 2.39 (t, 3J (H, H)=8Hz, 2H, γ-CH 2), 1.99-2.10 (m, 2H, β-CH 2); IR (KBr): ν=1651,1497,1446,1160,1067cm -1FABMS:217[M-SbCl 6 -]; Ultimate analysis (C 11H 13F 6N 4OSb): theoretical value C29.17, H2.87, N12.37;
Measured value C29.23, H2.85, N12.31.
Embodiment 6
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.SOCl 2，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-30℃，1.5hr.；
2,
Figure C9911354500143
, CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is , product analytical data is as follows: 1H NMR: δ=8.01-8.92 (m, 3H, aryl), 3.49 (t, 3J (H, H)=7Hz, 2H, α-CH 2), 2.86 (s, 3H, CH 3), 2.39 (t, 3J (H, H)=8Hz, 2H, γ-CH 2), 2.00-2.11 (m, 2H, β-CH 2); IR (KBr): ν=1650,1490,1446,1065,760,630cm -1FABMS:218[M-SbCl 6 -]; Ultimate analysis (C 10H 12Cl 6N 5OSb): theoretical value C21.73, H2.17, N12.66;
Measured value C21.56, H2.07, N12.71.
Embodiment 7
Reactions steps is with embodiment 1, and different is that acid amides is
Figure C9911354500151
,, reaction reagent and reaction conditions:
1、a.ClCOCl，CHCl 3，r.t.，1hr.；
b.SbCl 5/CH 2Cl 2，-30℃，2hr.；
2, , CH 3CN ,-35 ℃ → r.t., the 2hr. reaction product is
Figure C9911354500153
, the product data are as follows: 1H NMR: δ=2.00-2.11 (m, 2H, β-H), 2.39-2.40 (m, 2H, γ-H), 2.83 (m, 4H, 2CH 2), 2.87 (s, 3H, CH 3), 3.49-3.59 (m, 2H, α-CH 2); FABMS:197[M-SbCl 6 -]; Ultimate analysis (C 9H 13Cl 6N 2O 3Sb): theoretical C20.33, H2.44, N5.26;
Measured value C20.19, H2.45, N5.39.
Embodiment 8
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.ClCOCOCl，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-15℃，3hr.；
2, , CH 3CN ,-25 ℃ → r.t., the 2.5hr. reaction product is
Figure C9911354500163
, product analytical data is as follows: 1H NMR: δ=1.89-2.00 (m, 2H, β-H), 2.19 (t, 2H, γ-H), 2.89 (s, 3H, N-CH 3), 2.87 (s, 3H, CH 3), 3.38-3.48 (t, 2H, α-H), 7.58-8.46 (m, 3H, aryl); FABMS:285[M-SbCl 6 -]; Ultimate analysis (C 12H 12F 3Cl 6N 4OSb): theoretical value C23.25, H1.94, N9.03;
Measured value C23.06, H1.90, N9.21.
Embodiment 9:
Reactions steps is with embodiment 1, and different is that acid amides is
Figure C9911354500164
, reaction reagent and reaction conditions:
1、a.Cl 3COCOCCl 3，CH 2Cl 2，r.t.，0.5hr.；
b.SbCl 5/CHCl 3，-30℃，2.5hr.；
2, , CH 3CN ,-30 ℃ → r.t., the 2hr. reaction product is
Figure C9911354500172
, product analytical data is as follows: 1H NMR: δ=4.19-4.29 (m, 4H, α-H), 3.34-3.44 (m, 4H, β-H), 1.14 (s, 3H, CH 3); FABMS:280[M-SbCl 6 -]; Ultimate analysis (C 12H 11F 5Cl 6NOSb): theoretical value C23.44, H1.79, N2.28;
Measured value C23.49, H1.64, N2.38.
Embodiment 10
Reactions steps is with embodiment 1, and different is that acid amides is
Figure C9911354500173
, reaction reagent and reaction conditions:
1、a.POCl 3，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-25℃，2hr.；
2,
Figure C9911354500174
, CH 3CN ,-25 ℃ → r.t., the 1hr. reaction product is , product analytical data is as follows: 1H NMR: δ=6.59-8.39 (m, 14H, aryl), 1.22 (s, 3H, CH 3); FABMS:333[M-SbCl 6 -]; Ultimate analysis (C 20H 17C L6N 2O 3Sb): theoretical value C35.98, H2.55, N4.19;
Measured value C35.81, H2.66, N4.35.
Embodiment 11
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.ClCOCl，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-30℃，1.5hr.；
2,
Figure C9911354500183
, pyridine, CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is , product analytical data is 1H NMR: δ=4.50-4.60 (m, 4H, α-H), 2.41 (m, 4H, β-H), 1.74 (m, 2H γ-H), 7.42-7.73 (m, 3H, aryl); FABMS:374[M-SbCl 6 -], 376[M+2-SbCl 6 -]; Ultimate analysis (C 15H 15F 6C L7NOSb): theoretical value C25.41, H2.12, N1.97;
Measured value C25.33, H2.05, N2.11.
Embodiment 12:
Reactions steps is with embodiment 1, and different is that acid amides is
Figure C9911354500191
, reaction reagent and reaction conditions:
1、a.ClCOCOCl，CH 2Cl 2，r.t.，1hr.；
b.NaBPh 4/CHCl 3，-35℃，1.5hr.；
2, , NEt 3CH 3CN ,-35 ℃ → r.t., the 3hr. reaction product is , product analytical data is as follows: 1H NMR: δ=3.81 (q, 4H, α-H), 1.29 (t, 6H, β-H), 7.20-8.06 (m, 9H, aryl); FABMS:323[M-BPh 4 -]; Ultimate analysis (C 42H 39N 4O 2B): theoretical value C52.26, H4.04, N5.80;
Measured value C52.03, H3.94, N5.99.
Embodiment 13
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.Cl 3COCOCCl 3，CH 2Cl 2，r.t.，.；
B. (CF 2SO 2) 2O or CF 3SO 3Na/CHCl 3,-30 ℃, 2.5hr.;
2,
Figure C9911354500202
, CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is , product analytical data is as follows: 1H NMR: δ=7.51-8.63 (m, 2H, aryl),, 4.95 (m, 2H, α-H), 2.61 (m, 2H, β-H), 1.72 (m, 2H, γ-H), 2.01 (m, 2H, δ-H); FABMS:408 (M-CF 3SO 3 -)
Embodiment 14
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.POCl 3，CH 2Cl 2，r.t.，1hr.；
b.AgSbF 6/CHCl 3，-25℃，3hr.；
2,
Figure C9911354500211
, CH 3CN .-35 ℃ → r.t. of two different basic propyl group ethylamines, the 2hr. reaction product is , the product data are as follows: 1H NMR: δ=4.28 (q, 2H, CH 2-CH 3), 1.30 (t, 3H, CH 2-CH 3), 1.85 (m, 4H, α-H), 1.86 (m, 4H, β-H), 1.60 (m, 4H, γ-H), 7.37-7.52 (m, 4H, aryl), 6.19 (s, 1H); FABMS:411[M-SbF 6 -]; Ultimate analysis (C 19H 22F 9N 4O 3Sb): theoretical value C35.27, H3.40, N8.66;
Measured value C35.31, H3.33, N8.74.
Embodiment 15
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.SOCl 2，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-30℃，1.5hr
2,
Figure C9911354500221
, CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is , the product data are as follows: 1H NMR: δ=3.77 (q, 2H, CH 2CH 3), 1.29 (t, 3H, CH 2CH 3), 5.10 (m, 2H, α-H), 2.20 (m, 2H, δ-H), 1.86-2.28 (s, 6H, CH 3); FABMS:407[M-BF 4 -], 409[M-BF 4 -+ 2], 411[M-BF 4 -+ 4], 413[M-BF 4 -+ 6]; Ultimate analysis (C 15H 15F 4Cl 4N 4OB): theoretical value C36.33, H3.02, N11.29;
Measured value C36.21, H3.03, N11.19.
Embodiment 16
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.ClCOCOCl，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-20℃，1.5hr.；
2,
Figure C9911354500231
, N-methylmorphine woods, CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is
Figure C9911354500232
, the product data are as follows: 1H NMR:=2.20-2.72 (m, 2H, δ-H), 5.74 (m, 1H, γ-H), 6.28 (m, 1H, β-H), 4.32-4.42 (m, 2H, α-H), 3.55 (s, 3H, N-CH 3), 7.89-7.99 (m, 4H, aryl); FABMS:257[M-SbCl 6 -] ultimate analysis (C 13H 13Cl 6N 2O 3Sb): theoretical value C26.93, H2.24, N4.83;
Measured value C26.88, H2.26, N4.98.
Embodiment 17
Reactions steps is with embodiment 1, and different is that acid amides is
Figure C9911354500233
, reaction reagent and reaction conditions:
1、a.ClCOCl，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-30℃，1.5hr.；
2,
Figure C9911354500241
CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is , product analytical data is as follows: 1H NMR: δ=6.72-9.09 (m, 5H, aryl), 3.58 (s, 3H, CH 3), 3.44 (s, 3H, CH 3); FABMS:426[M-SbCl 6 -]; Ultimate analysis (C 16H 11F 5Cl 6N 3O 5Sb): theoretical value C25.26, H1.45, N5.52;
Measured value C25.11, H1.39, N5.53.
Embodiment 18
Reactions steps is with embodiment 1, and different is that acid amides is , reaction reagent and reaction conditions:
1、a.POCl 3，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-10℃，1.5hr.；
2,
Figure C9911354500251
, CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is , product analytical data is as follows: 1H NMR: δ=3.32-3.42 (m, 4H, β-H), 4.13-4.23 (m, 4H, α-H), 8.56 (s, 1H); FABMS:346[M-SbCL 6 -], 348[M-SbCL 6 -+ 2], 350[M-SbCL 6 -+ 4], 352[M-SbCL 6 -+ 6], 354[M-SbCL 6 -+ 8]; Ultimate analysis (C 11H 9Cl 11NOSb): theoretical value C19.33, H1.32, N2.05;
Measured value C19.30, H1.33, N2.11.
Embodiment 19
Reactions steps is with embodiment 1, and different is that acid amides is ,, reaction reagent and reaction conditions:
1、a.POCl 3，CH 2Cl 2，r.t.，1hr.；
b.SbCl 5/CHCl 3，-30℃，1.5hr.；
2,
Figure C9911354500261
, N-methylpyrazole, CH 3CN ,-50 ℃ → r.t., the 2-5hr. reaction product is
Figure C9911354500262
, product analytical data is as follows: 1H NMR: δ=3.56 (q, 2H, CH 2CH 3), 1.29 (t, 3H, CH 2CH 3), 1.24 (m, 4H, α-H), 1.01 (m, 4H, β-H), 0.65 (m, 2H, γ-H), 7.25-7.64 (m, 3H, aryl); FABMS:354[M-SbCL 6 -] ultimate analysis (C 16H 18F 6C L6NOSb): theoretical value C27.90, H2.61, N2.03;
Measured value C27.99, H2.54, N1.92.
Embodiment 20
Reactions steps is with implementation column 1, and different is that acid amides is
Figure C9911354500263
, reaction reagent and reaction conditions:
1、a.POCl 3，CH 2Cl 2，r.t.，1hr.；
b.CF 3SO 3Na/CHCl 3，-30℃，1.5hr.；
2, , CH 3CN ,-40 ℃ → r.t., the 3hr. reaction product is
Figure C9911354500272
, product analytical data is as follows: 1H NMR: δ=2.79 (m, 2H, γ-H), 6.23 (m, 1H, β-H), 6.21 (m, 1H, α-H), 3.65 (s, 3H, N-CH 3), 9.10-9.51 (m, 2H, aryl); FABMS:305[M-CF 3SO 3 -] ultimate analysis (C 12H 9F 3N 6O 8S): theoretical value C31.74, H1.98, N18.50;
Measured value C31.75, H1.99, N18.37.
Embodiment 21
Reactions steps is with embodiment 1, and different is that acid amides is
Figure C9911354500273
, reaction reagent and reaction conditions:
1, a. triphosgene, CH 2Cl 2, r.t..;
b.SbCl 5/CHCl 3，-20℃，1.5hr.；
2,
Figure C9911354500274
, NEt 3, CH 3CN ,-30 ℃ → r.t., the 3hr. reaction product is , product analytical data is as follows: 1H NMR: δ=3.99 (s, 3H ,-CH 3), 1.26 (s, 3H ,-CH 3), 3.53 (s, 3H ,-CH 3), 3.39 (s, 3H ,-CH 3), 2.63 (s, 3H ,-CH 3); FABMS:227[M-SbCl 6 -] ultimate analysis (C 9H 15Cl 6N 4O 3Sb): theoretical value C19.24, H2.67, N9.97;
Measured value C19.36, H2.64, N9.88

Claims (4)

1. cationic imide as polypeptide condensing agent is characterized in that general molecular formula is:
Figure C9911354500021
R wherein 1, R 2, R 3=H, C nH 2n+1, phenyl, substituted-phenyl, described n=1-5, described substituting group are F or CF 3,
Figure C9911354500022
R wherein 5, R 6=CF 3, NO 2, X=CH, N;
Figure C9911354500023
R wherein 7, R 8=H, C nH 2n+1, COOEt, COOCH 3, CF 3, NO 2, n as previously mentioned;
Figure C9911354500024
R wherein 9, R 10=NO 2, CF 3
Figure C9911354500025
Perhaps R 1And R 3Form propylidene, R 2=methyl,
Figure C9911354500026
Figure C9911354500027
Perhaps R 1And R 3Form butylidene, R 2=phenyl,
Figure C9911354500028
Perhaps R 1And R 3Form propenylidene, R 2=methyl,
Figure C9911354500029
Perhaps R 1And R 3Form crotonylidene, R 2=methyl, Perhaps R 1And R 3Form the crotonylidene that dimethyl replaces, R 2=C 2H 5,
Figure C9911354500032
Perhaps R 1And R 3Form pentylidene, R 2=ethyl, Perhaps R 1And R 2Form butylidene, R 3=phenyl, Perhaps R 1And R 2Form butylidene, R 3=methyl,
Figure C9911354500035
Perhaps R 1And R 2Form butylidene, R 3=H,
Figure C9911354500036
Perhaps R 1And R 2Form pentylidene, R 3=CH 2Cl,
Figure C9911354500037
Perhaps R 1And R 2Form hexylidene, Perhaps R 1, R 2=methyl, R 3=H, Perhaps R 1, R 2=phenyl, R 3=CH 3,
Figure C99113545000310
Perhaps R 1, R 2=CH 3,
Figure C99113545000311
A=SbCl 6, SbF 6, CF 3SO 3, PF 6, BPh 4, BF 4
2. cationic imide as polypeptide condensing agent as claimed in claim 1 is characterized in that molecular structural formula is:
Figure C99113545000312
Figure C9911354500041
3. the synthetic method of cationic imide as polypeptide condensing agent as claimed in claim 1, it is characterized in that by corresponding amide at first-30 ℃-0 ℃ following and chlorination reagent reaction, then after-10 ℃-50 ℃ the organic solvent of dropping stablizer reacts down, further obtain corresponding condensing agent with the activating component reaction again, reaction formula is as follows:
Figure C9911354500042
R wherein 1, R 2, R 3, R 4, A according to claim 1, chlorination reagent is: Cl 3COCOOCCl 3, POCl 3, SOCl 2, ClCOCl, ClCOCOCl; Stablizer is: SbCl 5, AgSbF 6, KPF 6, NaBPh 4, AgBF 4, CF 3SO 3Na; Organic solvent is a polar aprotic solvent; Described activating component is KR 4Or HR 4+ organic bases, wherein R 4According to claim 1.
4. the synthetic method of cationic imide as polypeptide condensing agent as claimed in claim 3 is characterized in that described organic bases is triethylamine, diisopropyl ethyl amine, pyridine, N-methylmorpholine, N-Methylimidazole.
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