CN1093534C - Cationic polypeptide condensing agent of pyridine, its synthesizing process and its application - Google Patents
Cationic polypeptide condensing agent of pyridine, its synthesizing process and its application Download PDFInfo
- Publication number
- CN1093534C CN1093534C CN 99113888 CN99113888A CN1093534C CN 1093534 C CN1093534 C CN 1093534C CN 99113888 CN99113888 CN 99113888 CN 99113888 A CN99113888 A CN 99113888A CN 1093534 C CN1093534 C CN 1093534C
- Authority
- CN
- China
- Prior art keywords
- condensing agent
- pyridine
- reaction
- polypeptide
- sbcl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Peptides Or Proteins (AREA)
Abstract
The present invention relates to a cationic polypeptide condensing agent of pyridine, a synthesizing method and the application thereof. The molecule formula is disclosed in the right upper formula. After 2-halogen pyridine reacts with an N-alkyl reagent under the condition of 0 to 70 DEG C, the 2-halogen pyridine reacts with an activation component under the condition of-30 DEG C to 25 DEG C for obtaining the corresponding cationic polypeptide condensing agent of pyridine. The polypeptide condensing agent can be used for synthesizing polypeptide. The performance of the polypeptide condensing agent is superior to that of a urea cationic condensing agent generally used and a phosphorus cationic condensing agent generally used; the polypeptide condensing agent can be used for synthesizing a liquid phase and a solid phase. The present invention has the advantages of simple and convenient synthesis, easy acquirement of raw material, stability at room temperature, high reactivity on application, small racemization, etc., and can be widely applied to the synthesis of polypeptide polyamide, ester and activation ester.
Description
The present invention relates to a class polypeptide condensing agent, i.e. pyridine positive ion type polypeptide condensing agent, synthetic and application.
Along with the development of polypeptide and protein chemistry, people design, have synthesized polytype condensing agent to satisfy the requirement of polypeptide and protein synthesis.For example the condensing agent dicyclohexylcarbodiimide DCC that at first proposed by Sheehan and Hess is just very representative nineteen fifty-five, still is widely used so far.But DCC is used for the synthetic meeting of polypeptide as condensing agent produces a lot of side reactions, 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 DCC 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 DCC 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 DCCI for this reason, some water miscible carbodiimides have been developed, as N-cyclohexyl-N '-(4-diethylaminocyclohexyl)-carbodiimide, N-cyclohexyl-N '-[2-(4-methyl morpholini)-ethyl] carbodiimide tosylate and N-ethyl-N '-(3-dimethyl aminopropyl)-carbodiimide replace DCC, but are not widely used.
From 1975, people such as Castro design, synthesized since first phosphorus positive ion type condensing agent BOP based on HOBt, be that the phosphorus positive ion type and the carbonium ion type reagent of Acibenzolar develops rapidly with I-hydroxybenzotriazole HOBt, as Coste, J., Le-Nguyen, D.AndCastro, 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.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 young ' s test, Chen, S.Q.andXu, J.C., Tetrahedron Lett., 1992,33,647-650 finds that with bop reagent 39.8% racemization product is arranged, and HBTU reagent also has 25.4% racemization product.Galpin, I.J., Gordon, P.F., Ramage, R.and Thorpe, W.D., Tetrahedron, 1976, people such as Galpin is reported in the process with BOP condensation Z-Gly-Ala-OH and H-Leu-OCH2Ph in 32,2417 has 29% racemization, Steinauer, R., Chen, F.M.F.and Benoiton, N.L., Int.J.Peptide Protein 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 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), MayflowerScientific Ltd., 1996, p88; Deng in disclosed AOP, PyAOP, HATU, HAPipU, HAPyU, HAMDU, reagent such as HAMTU.This type of reagent has higher activity and less racemization based on the condensing agent of HOBt accordingly, but preparation is difficult, and less stable, price are also relatively more expensive.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.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＝C，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 passivation Wijkmans, J.C.H.M., Blok, F.A.A., van derMarel, G.A., van Boom, J.H.and Bloemhoff, W., Tetrahedron Lett., 1995,36,4643; Wijkmans, J.C.H.M., Kruijtzer, A.W., van derMarel, G.A., van Boom, J.H.and Bloemhoff, W., Recl.Trav.Chim.Pays-Bas, 1994, partly introduce trifluoromethyl at Acibenzolar in 113,394, electron-withdrawing substituents such as nitro improve the activity of condensing agent.We are with one in the urea positive ion condensing agent amino activity that further improves condensing agent that replaces with alkyl, aryl even hydrogen in ZL99113545.8, successfully designed and synthesized a class cationic imide type condensing agent, experimental results show that this class condensing agent has preferable performance.
Though have preferable performance in the condensation of this type of condensing agent between common amino acid, can but can not be satisfactory for the synthetic result of the sterically hindered polypeptide that has living space.We are on the basis of the urea of having developed, phosphorus and cationic imide type condensing agent for this reason, and pyridine positive ion type polypeptide condensing agent has been synthesized in design.
Purpose of the present invention just provides the novel pyridine positive ion type polypeptide condensing agent of a class, and its general molecular formula is:
R wherein
1Be H, C
nH
2n+1, the integer of n=1-5, phenyl, substituted-phenyl, described substituted-phenyl recommended structure formula is
X is F, Cl, Br; R
2For
R wherein
5, R
6Be CF
3, NO
2, X ' is CH, N,
R wherein
7, R
8Be H, C
nH
2n+1, the integer of n=1-5, COOEt, COOR, CF
3, NO
2, described R is C
nH
2n+1, the integer of n=1-5,
R wherein
9, R
10Be NO
2, CF
3,
R
2Also can be F, Cl, Br; A is SbCl
6, SbF
6, CF
3SO
3, PF
6, BPh
4, BF
4
Another object of the present invention has provided the corresponding synthetic method of new pyridine positive ion type polypeptide condensing agent, be raw material promptly with 2-halogen pyridine, under 0-70 ℃ the condition with N-alkylating reagent reaction after, and/or under-30-25 ℃ temperature, obtain corresponding condensing agent with corresponding activating component reaction.Reaction formula is as follows:
Wherein: the N-alkylating reagent is (R
1)
3O
+BF
4 -, (R
1)
3O
+SbCl
6 -, (R
1)
3O
+SbF
6 -, (R
1)
3O
+BPh
4 -, CF
3SO
3R
1, (R
1)
3O
+PF
6 -Organic solvent is a polar aprotic solvent; Activating component is the active ingredient that contains hydroxyl, i.e. KR
2' or HR
2'+organic bases, R
2' be
R wherein
5, R
6Be CF
3, NO
2, X ' is CH, N,
R wherein
7, R
8Be H, C
nH
2n+1, the integer of n=1-5, COOEt, COOR, CF
3, NO
2, R as previously mentioned.
R
9, R
10Be NO
2, CF
3,
Organic bases is triethylamine, diisopropyl ethyl amine, pyridine, N-methylmorpholine, N-Methylimidazole.
Work as R
2During for the pyridine positive ion polypeptide condensing agent of F, Cl, Br, its synthetic method is to be raw material with 2-halogen pyridine, is obtaining under the condition of organic solvent, 0-70 ℃ with after the reaction of N-alkylating reagent, and reaction formula is as follows:
Wherein: X is F, Cl, Br; R
1Be H, C
nH
2n+1, the integer of n=1-5, phenyl, substituted-phenyl, the structure that described substituted-phenyl is recommended is as previously mentioned; Organic solvent is a polar aprotic solvent; The N-alkylating reagent is (R
1)
3O
+BF
4 -, (R
1)
3O
+SbCl
6 -, (R
1)
3O
+SbF
6 -, (R
1)
3O
+BPh
4 -, CF
3SO
3R
1, (R
1)
3O
+PF
6 -
Another object of the present invention is that such positive ion type polypeptide condensing agent can be used for the synthetic of polypeptide, especially R
2Be the pyridines positive ion polypeptide condensing agent of F, Cl, Br, it is mainly used in the sterically hindered that has living space and contains N-alkylation amino acid and α, the amino acid whose polypeptide of α-dialkyl groupization synthetic.This class condensing agent is used for the general synthesis step of polypeptide when synthetic: with the amino acid or the polypeptide fragment of N-end protection, the amino acid of C-end protection or the hydrochloride of polypeptide fragment ester or trifluoroacetate and condensing agent are dissolved in DMF or CH
2Cl
2In, slowly adding organic bases diisopropyl ethyl amine or 2 at low temperatures, the 6-lutidine added the back low-temp reaction five minutes, and room temperature reaction by thin-layer chromatography identification reaction terminal point, promptly obtains corresponding polypeptide then.
New pyridine positive ion type polypeptide condensing agent provided by the present invention still all is better than 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.Especially R
2Be the pyridine positive ion polypeptide condensing agent of F, Cl, Br, its sterically hindered that can be applicable to have living space contains N-alkylation amino acid and α, and the amino acid whose polypeptide of α-dialkyl groupization 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
At ambient temperature the 2-bromo-pyridine of 0.0176mol is joined the Et of 0.0176mol
3O
+BF
4 -ClCH
2CH
2In the Cl solution, oil bath is heated to 60 ℃, reacts ten minutes, naturally cools to room temperature, has large-tonnage product to separate out, and getting clear crystal 2-bromo-1-ethylpyridine positive ion a tetrafluoro borate BEP is 4.588g, yield 95.2%, mp 103-104 ℃;
1H NMR (300MHz, d
6-acetone, TMS): 1.69 (t, J=7.3Hz, 3H,
CH
2CH
3)，5.01(q，J＝7.3Hz，CH
2CH
3)，8.24(m，1H，aryl)，
8.53-8.57(m，2H，aryl)，9.32(d，J＝6.9Hz，aryl)；IR(KBr)：ν＝3106，1617，1571，1500，1467，1296，1050，786，718，521cm
-1；FAB-MS：186[M-BF
4 -]，188[M-BF
4 -+2]。
Embodiment 2
2-fluoro-pyridine with 0.0539mol under 0 ℃ of condition joins 0.0539mol Et
3O
+BF
4 -CH
2Cl
2In the solution, one hour postcooling to 0 of room temperature reaction ℃ has large-tonnage product to separate out, clear crystal 2-fluoro-1-ethylpyridine positive ion a tetrafluoro borate 10.837g, yield 94.7%,
mp 38-40℃.
1H NMR(300MHz，d
6-acetone，TMS)：1.57(t，J(H，F)＝70.7Hz，
3J(H，H)＝7.3Hz，3H，CH
2CH
3)，4.62(q，J(H，F)＝141
Hz，
3J(H，H)＝7.3Hz，CH
2CH
3)，7.10-9.04(m，4H，
aryl).
19F NMR(CF
3COOH)：δ＝75.2ppm(s，1F)IR(KBr)：ν＝3039，1643，1587，1519，1475，11456，1307，1035，847，786，725，534，522cm
-1.FAB-MS：126[M-BF
4 -]
Embodiment 3
The first step reaction is with embodiment 2, the 2-fluoro-1-ethylpyridine positive ion hexa chloro-antimonate of 10.0mmol is dissolved in the dry acetonitrile of 30ml, stirring is cooled to-30 ℃, add 10.0mmol 1-hydroxyl-7-azepine benzotriazole sylvite, behind the low-temp reaction, remove ice bath, room temperature reaction 2-4 hour, filter, filtrate is concentrated into the crystalloid solid and separates out, and gets product 4.77 grams.Yield is 80%.
1H NMR：δ＝8.01-9.12(m，7H，aryl)，4.79(q，
3J(H，H)＝7Hz，2H，N-CH
2)，1.50(t，
3J(H，H)＝7Hz，3H，β-CH
3)ppm；
FABMS：242[M-SbCl
6 -]；
elemental analysis calcd.for C
12H
12Cl
6N
5OSb(576.677)：
C 24.99，H 2.10，N 12.14
found：C 25.21，H 2.14，N 11.98
Embodiment 4
With embodiment 3, temperature of reaction that different is is with embodiment 1, the second step reactions steps and condition for the first step reaction-20-20 ℃, and N-alkylating reagent Et
3O
+SbF
6 -, active constituent is
Product is
1H NMR：δ＝8.12-9.04(m，6H，aryl)，4.95(q，J＝7Hz，2H，N-CH
2)，1.68(t，J＝7Hz，3H，β-CH
3)ppm；
FABMS：354[M-SbF
6 -]；elemental analysis calcd.for C
14H
11F
9N
5O
5Sb(589.957)：
C 28.50，H 1.88，N 11.87found：C 28.31，H 2.04，N 11.99
Embodiment 5
With embodiment 3, different is that temperature of reaction is-25 ℃-15 ℃, N-alkylating reagent Et with embodiment 2, the second step reactions steps and condition for the first step reaction
3O
+SbCl
6 -, active constituent is
Product is
1HNMR：δ＝8.05-9.02(m，4H，aryl)，6.57(s，1H，aryl)，4.90(q，J＝7Hz，2H，N-CH
2)，4.27(q，J＝7Hz，2H，CH
2)，1.65(t，J＝7Hz，3H，β-CH
3)，1.30(t，J＝7Hz，3H，CH
3)ppm；
FABMS：354[M-SbCl
6 -]；
elemental analysis calcd.for C
12H
15Cl
6N
4O
3Sb(597.692)：
C 24.11，H 2.53，N 9.37
found：C 24.00，H 2.53，N 9.21
Embodiment 6
The first step reaction is with embodiment 2, and the organic solvent that is not both is CH
3CN, the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is-15 ℃-25 ℃, N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
, product is
1H NMR：δ＝8.11-9.14(m，4H，aryl)，4.97(q，J＝7Hz，2H，N-CH
2)，1.71(t，J＝7Hz，3H，β-CH
3)ppm；
FABMS：377[M-SbCl
6 -]；379[M-SbCl
6 -+2]；381[M-SbCl
6 -+4]；383[M-SbCl
6 -+6]；
elemental analysis calcd.for C
13H
9Cl
10N
4OSb(713.470)：
C 21.89，H 1.27，N 7.85
found：C 22.03，H 1.25，N 7.79
Embodiment 7
The first step reaction is with embodiment 1, and different is that organic solvent is a tetrahydrofuran (THF), and the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is-10 ℃-20 ℃, N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
+ diisopropyl ethyl amine, product is
1H NMR：δ＝7.79-9.02(m，8H，aryl)，4.88(q，J＝7Hz，2H，N-CH
2)，1.69(t，J＝7Hz，3H，β-CH
3)ppm；
FABMS：269[M-SbCl
6 -]；
elemental analysis calcd.for C
15H
13Cl
6N
2O
3Sb(603.696)：
C 29.84，H 2.17，N 4.64
found：C 30.12，H 2.26，N 4.65
Embodiment 8
The first step reaction is with embodiment 1, and different is that the 2-haloperidid is
Temperature of reaction is 0-70 ℃, and organic solvent is an ethyl acetate, and the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is-5 a ℃-room temperature, N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
Product is
1H NMR：δ＝8.19-9.21(m，6H，aryl)，5.03(q，J＝7Hz，2H，N-CH
2)，1.77(t，J＝7Hz，3H，β-CH
3)ppm；
FABMS：358[M-SbCl
6 -]；
elemental analysis calcd.for C
14H
11Cl
6F
3N
3O
5Sb(692.669)：
C 24.28，H 1.60，N 6.07
found：C 24.34，H 1.66，N 6.17
Embodiment 9
The first step reaction is with embodiment 1, and different is that the 2-haloperidid is
Temperature of reaction is 0-70 ℃, and organic solvent is CH
2Cl
2, the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is-5 a ℃-room temperature, N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
Product is
1H NMR：δ＝7.97-9.02(m，4H，aryl)，4.96(q，J＝7Hz，2H，N-CH
2)，1.71(t，J＝7Hz，3H，β-CH
3)ppm；FABMS：370[M-SbCl
6 -]；372[M-SbCl
6 -+2]；374[M-SbCl
6 -+4]；376[M-SbCl
6 -+6]；378[M-SbCl
6 -+8]；elemental analysis calcd.for C
13H
9Cl
11NOSb(706.903)：
C 22.09，H 1.28，N 1.98found：C 22.31，H 1.30，N 1.98
Embodiment 10
The first step reaction is with embodiment 2, and different is that organic solvent is CH
3CN, the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is-10 a ℃-room temperature, N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
+ pyridine, product is
1H NMR：δ＝7.45-8.95(m，7H，aryl)，4.90(q，J＝7Hz，2H，N-CH
2)，1.66(t，J＝7Hz，3H，β-CH
3)ppm；FABMS：336[M-SbCl
6 -]；elemental analysis calcd.for C
15H
12Cl
6F
6NOSb(670.674)：
C 26.86，H 1.80，N 2.09found：C 26.66，H 1.62，N 2.13
Embodiment 11
The first step reaction is with embodiment 2, and different is that temperature of reaction is 0-40 ℃, and organic solvent is a tetrahydrofuran (THF), and the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is 0-25 ℃, N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
Product is
1H NMR: δ=8.23-9.24 (m, 6H, aryl), 5.16 (q, J=7Hz, 2H, N-CH
2), 1.80 (t, J=7Hz, 3H, β-CH
3) ppm; FABMS:290[M-SbCl
6 -]; Elemental analysis calcd.for C
13H
9Cl
6F
5NOSb (624.63):
C 25.00，H 1.45，N 2.24found：C 25.21，H 1.62，N 12.50
Embodiment 12
The first step reaction is with embodiment 2, and temperature of reaction that different is is a room temperature-50 ℃, and organic solvent is an ethyl acetate, and the second step reactions steps and condition are with embodiment 3, and that different is N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
+ N-methylmorpholine, product is
1H NMR: δ=8.01-8.99 (m, 4H, aryl), 4.98 (q, J=7Hz, 2H, N-CH
2), 2.75 (s, 3H, CH
3); 2.15 (s, 3H, CH
3) 1.62 (t, J=7Hz, 3H, β-CH
3) ppm; FABMS:247[M-SbCl
6 -]; Elemental analysis calcd.for C
12H
15Cl
6N
4O
2Sb (581.693):
C 24.78，H 2.60，N 9.63found：C 24.61，H 2.55，N 9.57
Embodiment 13
The first step reaction is with embodiment 1, and different is that the 2-haloperidid is
Temperature of reaction is 0-60 ℃, and organic solvent is CH
3CN, the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is-5 a ℃-room temperature, N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
Product is
1H NMR: δ=8.23-9.31 (m, 4H, aryl), 5.09 (q, J=7Hz, 2H, N-CH
2), 1.88 (t, J=7Hz, 3H, β-CH
3) ppm; FABMS:377[M-SbCl
6 -]; Elemental analysis calcd.for C
13H
9Cl
10N
4OSb (713.470):
C 21.89，H 1.27，N 7.85found：C 22.03，H 1.25，N 7.79
Embodiment 14
The first step reaction is with embodiment 2, and different is that organic solvent is an ethyl acetate, and the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is-25 a ℃-room temperature, N-alkylating reagent Et
3O
+SbCl
6 -, active constituent is
Product is
1H NMR：δ＝7.65-8.53(m，8H，aryl)，5.12(q，J＝7Hz，2H，N-CH
2)，1.91(t，J＝7Hz，3H，β-CH
3)ppm；FABMS：377[M-SbCl
6 -]；elemental analysis calcd.for C
14H
15Cl
6N
4O
2Sb(605.72)：
C 27.76，H 2.50，N 9.25found：C 27.60，H 2.25，N 9.06
Embodiment 15
The first step reaction is with embodiment 1, and different is that the 2-haloperidid is
Temperature of reaction is 10-70 ℃, and organic solvent is an ethyl acetate, and the second step reactions steps and condition are with embodiment 3, and different is that temperature of reaction is-20 a ℃-room temperature,, N-alkylating reagent CF
3SO
2OCH
2CH
2CH
2CH
2CH
3, active constituent is
Product is
1H NMR: δ=7.97-9.02 (m, 4H, aryl), 4.96 (q, J=7Hz, 2H, N-CH
2), 1.71 (t, J=7Hz, 3H, β-CH
3) ppm; FABMS:370[M-SbCl
6 -]; 372[M-SbCl
6 -+ 2]; 374[M-SbCl
6 -+ 4]; 376[M-SbCl
6 -+ 6]; 378[M-SbCl
6 -+ 8]; Elemental analysis calcd.for C
13H
9Cl
11NOSb (706.903):
C 22.09，H 1.28，N 1.98found：C 22.31，H 1.30，N 1.98
Embodiment 16
With embodiment 3, different is that temperature of reaction is-25 ℃-25 ℃, N-alkylating reagent CF with embodiment 2, the second step reactions steps and condition for the first step reaction
3SO
2OPh, active constituent is
Product is
1H NMR: δ=7.97-9.02 (m, 4H, aryl), 4.96 (q, J=7Hz, 2H, N-CH
2), 1.71 (t, J=7Hz, 3H, β-CH
3) ppm; FABMS:370[M-SbCl
6 -]; 372[M-SbCl
6 -+ 2]; 374[M-SbCl
6 -+ 4]; 376[M-SbCl
6 -+ 6]; 378[M-SbCl
6 -+ 8]; Elemental analysis calcd.for C
13H
9Cl
11NOSb (706.903):
C 22.09，H 1.28，N 1.98found：C 22.31，H 1.30，N 1.98
Embodiment 17
With embodiment 3, different is that temperature of reaction is-30 ℃-25 ℃, N-alkylating reagent CF with embodiment 1, the second step reactions steps and condition for the first step reaction
3SO
2OC
6H
4-Cl-p, active constituent is
Product is
1H NMR: δ=7.97-9.02 (m, 4H, aryl), 4.96 (q, J=7Hz, 2H, N-CH
2), 1.71 (t, J=7Hz, 3H, β-CH
3) ppm; FABMS:370[M-SbCl
6 -]; 372[M-SbCl
6 -+ 2]; 374[M-SbCl
6 -+ 4]; 376[M-SbCl
6 -+ 6]; 378[M-SbCl
6 -+ 8]; Elemental analysis calcd.for C
13H
9Cl
11NOSb (706.903):
C 22.09，H 1.28，N 1.98found：C 22.31，H 1.30，N 1.98
Embodiment 18
With following pyridine polypeptide condensing agent:
Synthetic N-alkylation amino acid and the α of containing; the synthesis step of α-dialkyl group amino acid polypeptide is: with the amino acid or the polypeptide fragment of 1mol N-end protection, the amino acid of 1mol C-end protection or the hydrochloride of polypeptide fragment ester or trifluoroacetate and 1mol condensing agent are dissolved in DMF or CH
2Cl
2In, 0 ℃ of low temperature--slowly add the organic bases diisopropyl ethyl amine or 2 of 3mol under 10 ℃ the condition, the 6-lutidine added the back low-temp reaction five minutes, room temperature reaction then, by thin-layer chromatography identification reaction terminal point, yield results is as follows successively:
Table 1: condensing agent synthesizes polypeptide productive rate table
Annotate:
b* represent the CO-NH key to form position, the equal warp of all products
1H NMR, EIMS and other modes identify that structure is correct.
bFurther identify through HMQC and ESI-MS.
| Entr y | Peptide a | Yield (%) | |||
| 1 | Fmoc-Nva-Sar-Obzl | 97.6 | 96.5 | 97.2 | 95.4 |
| 2 | Z-MeVal*-MeVal-Ome | 95.4 | 94.7 | 96.3 | 93.2 |
| 3 | Fmoc-Val*-Meval- OCH 3 | 88.4 | 90.4 | 89.7 | 87.8 |
| 4 | Boc-Pro*-Pro-Obzl | 90.2 | 92.2 | 93.1 | 90.5 |
| 5 | Z-Aib*-Aib-OCH 3 | 95.8 | 94.8 | 95.4 | 96.3 |
| 6 | Fmoc-MeLeu*-MeVal- OBzl | 91.4 | 90.7 | 92.8 | 91.5 |
| 7 | Fmoc-MeLeu*-MeLeu- MeVal-OBzl | 48.1 | 60.7 | 58.6 | 53.2 |
| 8 b | Fmoc-D-Ala*-MeLeu- MeLeu-MeVal-OBzl | 94.3 | 95.2 | 93.4 | 92.1 |
Claims (6)
1, a kind of pyridines positive ion type polypeptide condensing agent is characterized in that general molecular formula is:
R wherein
1Be H, C
nH
2n+1, the integer of n=1-5, phenyl, substituted-phenyl, described substituted-phenyl structural formula is
X is F, Cl, Br; R
2Be F, Cl, Br,
R wherein
5, R
6Be CF
3, NO
2, X ' is CH, N,
R wherein
7, R
8Be H, C
nH
2n+1, the integer of n=1-5, COOEt, COOR, CF
3, NO
2, described R is C
nH
2n+1, the integer of n=1-5,
R
9, R
10Be NO
2, CF
3,
A is SbCl
6, SbF
6, CF
3SO
3, PF
6, BPh
4, BF
4
2, a kind of synthetic method of new pyridine positive ion type polypeptide condensing agent, it is characterized in that with 2-halogen pyridine be raw material, under the condition of organic solvent, 0-70 ℃ with the reaction of N-alkylating reagent after, and/or under-30-25 ℃ temperature, obtain corresponding condensing agent with corresponding activating component reaction, reaction formula is as follows:
Wherein: X is F, Cl, Br; R
1Be H, C
nH
2n+1, the integer of n=1-5, phenyl, substituted-phenyl, described substituted-phenyl is according to claim 1; Described N-alkylating reagent is (R
1)
3O
+BF
4 -, (R
1)
3O
+SbCl
6 -, (R
1)
3O
+SbF
6 -, (R
1)
3O
+BPh
4 -, CF
3SO
3R
1, (R
1)
3O
+PF
6 -Described activating component is the active ingredient that contains hydroxyl, i.e. KR
2' or HR
2'+organic bases,
R
2' be
R wherein
5, R
6Be CF
3, NO
2, X ' is CH, N,
R wherein
7, R
8Be H, C
nH
2n+1, the integer of n=1-5, COOEt, COOR, CF
3, NO
2, described R according to claim 1,
R
9, R
10Be NO
2, CF
3,
3, pyridine positive ion type polypeptide condensing agent as claimed in claim 1 is characterized in that wherein R
2Be F, Cl, Br.
4, the synthetic method of pyridine positive ion type polypeptide condensing agent as claimed in claim 2 is characterized in that organic solvent is a polar aprotic solvent.
5, the synthetic method of pyridine positive ion type polypeptide condensing agent as claimed in claim 2 is characterized in that organic bases is a triethylamine, diisopropyl ethyl amine, pyridine, N-methylmorpholine, N-Methylimidazole.
6, the purposes of pyridine positive ion type polypeptide condensing agent as claimed in claim 3, the sterically hindered that it is characterized in that being applied to have living space contains N-alkylation amino acid and α, the amino acid whose polypeptide of α-dialkyl groupization synthetic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99113888 CN1093534C (en) | 1999-07-19 | 1999-07-19 | Cationic polypeptide condensing agent of pyridine, its synthesizing process and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99113888 CN1093534C (en) | 1999-07-19 | 1999-07-19 | Cationic polypeptide condensing agent of pyridine, its synthesizing process and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1243828A CN1243828A (en) | 2000-02-09 |
| CN1093534C true CN1093534C (en) | 2002-10-30 |
Family
ID=5277031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99113888 Expired - Fee Related CN1093534C (en) | 1999-07-19 | 1999-07-19 | Cationic polypeptide condensing agent of pyridine, its synthesizing process and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1093534C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE50108948D1 (en) * | 2000-12-20 | 2006-04-20 | Lanxess Deutschland Gmbh | 2-bromo / chloro-thiazolium salts and their use as condensation reagents |
-
1999
- 1999-07-19 CN CN 99113888 patent/CN1093534C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1243828A (en) | 2000-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11414375B2 (en) | Mild and efficient preparation method for α-acyloxyenamide compounds and use thereof in synthesis of amide and polypeptide | |
| CN1243779C (en) | Hydrophili polymer derirative having Y shaped branch, its preparation method, combined object with medicine molecule and medical compositon containing combined object | |
| WO2019198834A1 (en) | Method for producing leuprorelin | |
| CN1093534C (en) | Cationic polypeptide condensing agent of pyridine, its synthesizing process and its application | |
| EP0611774A1 (en) | Production of amides and peptides without racemization in the presence of catalytic amounts of a N-hydroxy-compound | |
| CN1102583C (en) | Cationic polypeptide condensing agent of thiazole, its synthesizing process and its application | |
| CA1331497C (en) | Guanidic compounds comprising a tetraphenylborate ion, process to prepare such compounds and their use for the synthesis of peptides | |
| CN1310898C (en) | Taxinol water soluble derivative | |
| TW202328164A (en) | Method for producing ganirelix or salt thereof | |
| CN1107676C (en) | Cationic imide as polypeptide condensing agent and its synthesis | |
| JP4734656B2 (en) | Method for producing PF1022 | |
| CN1104209A (en) | 2,4-diamino-3-hydroxycarboxylic acid derivatives | |
| Marinier et al. | The 2, 2, 2-trichloroethyl group for carboxyl protection during peptide synthesis | |
| JP6198222B2 (en) | Polyethylene glycol terminated with polyfunctional groups | |
| US6562944B1 (en) | Amide library formation using a “by-product-free” activation/coupling sequence | |
| US8841476B2 (en) | Preparation of crystalline ezatiostat hydrochloride ansolvate form D | |
| CN1934076A (en) | Method for producing semicarbazones | |
| US20240174713A1 (en) | Peptide synthesis method involving sterically hindered mixed anhydride intermediate | |
| US6794492B2 (en) | Perfluoroalkyl compounds and their methods of use and manufacture | |
| CN117924142A (en) | Liquid phase synthesis method of semaglutin side chain and synthesis method of semaglutin | |
| CN111978213B (en) | Multifunctional compound for polypeptide cyclization and preparation method and application thereof | |
| CN1203054C (en) | Novel benzoylurea compound and use thereof | |
| JP4949557B2 (en) | Peptide acylation method and novel acylating agent | |
| CN1684941A (en) | Method for producing acylated peptides | |
| JPH09255668A (en) | Production of bisoxazolines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |