CN101492415A - Pyridine-2-sulfuryl arginine derivative and method for preparing the same - Google Patents
Pyridine-2-sulfuryl arginine derivative and method for preparing the same Download PDFInfo
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- CN101492415A CN101492415A CNA2009101111640A CN200910111164A CN101492415A CN 101492415 A CN101492415 A CN 101492415A CN A2009101111640 A CNA2009101111640 A CN A2009101111640A CN 200910111164 A CN200910111164 A CN 200910111164A CN 101492415 A CN101492415 A CN 101492415A
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Abstract
A pyridine-2-sulfonyl arginine derivative and a preparation method thereof relate to the preparation of a pyridine-2-sulfonyl (Pyr) guanidine derivative, in particular to the pyridine-2-sulfonyl arginine derivative and the preparation method thereof. The invention provides a pyridine-2-sulfonyl arginine derivative which is obtained easily with low price, high yield and easy operation and the preparation method thereof. 2-sulphydryl pyridine is dissolved in organic solvent and stirred; sodium hypochlorite is added to be stirred to obtain mixed solution; the mixed solution is transferred to a separatory funnel to obtain an organic layer which is decompressed and concentrated to obtain light yellow oily pyridine-2-sulfonyl chloride; the pyridine-2-sulfonyl chloride and an arginine derivative with exposed guanido react in the organic solvent and alkali to obtain the pyridine-2-sulfonyl arginine derivative.
Description
Technical field
The present invention relates to the preparation of a kind of pyridine-2-sulfuryl (Pyr) guanidine derivative, especially relate to a kind of pyridine-2-sulfuryl arginine derivative and preparation method thereof.
Background technology
Because guanidine radicals:
Very strong alkalescence is arranged, and under general reaction conditions, arginic guanidine radicals is protected with protonated form usually, but the corresponding solubleness of derivative in organic solvent is very low, is unfavorable for synthesizing.In this case, guanidine radicals may take place partially acylated, and this is a greatest drawback.It would be desirable three nitrogen-atoms on the side chain are all protected that most of strategies are protection respectively still, although alkaline guanidine radicals is had a variety of guard methods, but up to the present, does not also have a kind of ideal guard method.
Classical guanidine radicals protection reagent mainly contains nitro ([1] K.Hofmann, W.D.Pekham, A.Rheiner, J.Am.Chem.Soc., 1956,78,238), carbamate ([2] L.Zervas, M.Winitz, J.P.Breensfein, J.Org.Chem., 1957,22,1515), benzenesulfonyl ([3] J.Ramachandran, C.H.Li, J.Org.Chem.1962,27,4006; [4] O.Nishimura, M.Fujino, Chem.Pharm.Bull.1976,24,1568; [5] H.Yajima, M.Takeyama, J.Kanaki, K.Mitani, J.Chem.Soc., Chem.Commun.1978,482; [6] M.Fujino, O.Nishimura, M.Wakimazu, C.Kitada, J.Chem.Soc., Chem.Commun.1980,668; [7] R.Ramage, J.Green, A.J.Blake, Tetrahedron 1991,47, and 6353; [8] L.A.Carpino, H.Shroff, S.A.Triolo, E.-S.M.E.Mansour; H.Wenschuh, F.Albericio, Tetrahedron Lett.1993,34; 7829) etc., still except benzenesulfonyl had certain application, other three classes protection reagent were difficult to be widely used.
Because independent benzenesulfonyl just can be realized the protection fully of guanidine radicals, therefore, this class protecting group is most widely used general.Although use the fragrant sulphonyl type of benzene to carry out N
ωSingle protection can not suppress lactan fully and generate, but collocation is used with HOBt, can obtain ideal effect.
The transformation of classical alkylsulfonyl all is to add electron-donating group on phenyl ring; help removing in the alkylsulfonyl acid; although a lot of scientists have studied Tos; Mbs, Mts, Mtr; Pmc; the acid proof difference of Pbf and Boc (referring to above-mentioned document [3]～[8]): this class protecting group is by introducing electron donating group on aromatic ring, the sensitivity to acid of aromatic base sulphonyl type protecting group is transformed, and they are Tos＜Mbs＜Mts＜Mtr＜Pmc＜Pbf to the susceptibility of acid in proper order.And summed up the precaution of collocation use each other, but these experiences may be difficult to all grasp concerning being engaged in polypeptide synthetic people for a long time.
Summary of the invention
The object of the present invention is to provide a kind of cheap and easy to get, pyridine-2-sulfuryl arginine derivative that productive rate is high, simple to operate and preparation method thereof.
The structural formula of pyridine-2-sulfuryl arginine derivative of the present invention is:
X=H wherein, Cbz, Boc, Fmoc etc.; Y=H, Me, Et, Bn, t-Bu etc.
The preparation method's of pyridine-2-sulfuryl arginine derivative of the present invention route is:
X=H wherein, Cbz, Boc, Fmoc, alkyl etc. are organic chain arbitrarily; Y=H, Me, Et, Bn, t-Bu etc. are organic chain arbitrarily.
The preparation method of pyridine-2-sulfuryl arginine derivative of the present invention may further comprise the steps:
1) the 2-mercaptopyridine is dissolved in the organic solvent, stirs, add clorox, stir, get mixed solution;
2) mixed solution is transferred in the separating funnel, got organic layer, concentrating under reduced pressure gets faint yellow oily thing pyridine-2-sulfuryl chlorine;
3) pyridine-2-sulfuryl chlorine and guanidine radicals is exposed arginine derivative reacts in organic solvent and alkali, pyridine-2-sulfuryl arginine derivative.
In step 1), described organic solvent preferably is selected from methylene dichloride, ethyl acetate, acetonitrile, toluene, a kind of in the acetate etc., or be selected from methylene dichloride, ethyl acetate, acetonitrile, toluene, the mixed solvent of a kind of and mineral acid in the acetate etc., the mixed solvent of preferred methylene dichloride and hydrochloric acid; The time of described stirring is preferably 15～40min.
In step 2) in, described separating funnel is cooling in advance preferably; The temperature of described concentrating under reduced pressure is preferably 10～15 ℃.
In step 3), described organic solvent preferably is selected from methylene dichloride, ethyl acetate, acetonitrile, tetrahydrofuran (THF), ethanol, acetone, the mixed solvent of a kind of and water in the acetate etc., the mixed solvent of preferred acetonitrile and water; Described alkali can be organic bases or mineral alkali arbitrarily, the oxyhydroxide of preferred as alkali.
As pyridine-2-sulfuryl guanidine radicals arginine is carried out peptide elongation, operable polypeptide condensing agent can be dicyclohexylcarbodiimide (DCC), isobutyl chlorocarbonate, the chloroformic acid tert-butyl ester, Vinyl chloroformate, HOSu, HOBt, HOOBt, Ph
3P-CCl
4, Ph
3P-C
2Cl
6The conventional synthetic method of polypeptide such as method, preferred DCC and HOSu collocation are used.
The pyridine-2-sulfuryl base uses the Mg-protonic solvent to remove, and obtains guanidine radicals exposed arginine and derivative thereof, and protonic solvent comprises: methyl alcohol, formic acid, conventional protonic solvent such as acetate, particular methanol.
The present invention has synthesized a kind of new two protection arginine, and under condensing agent and alkali effect, this pyridine-2-sulfuryl arginine derivative can generate the polypeptide that contains arginic full guard with amino acid and amino acid derivative condensation.The method of condensing that is suitable for comprises active ester method, and the DCC method is mixed the acid anhydride method, and polypeptide method of condensing commonly used such as triphenylphosphine-full halogenated hydrocarbon method all can well be used.
Pyridine-2-sulfuryl Quito peptide can utilize Mg-protonic solvent method to remove.
Compared with prior art, the present invention has following outstanding advantage:
1) the pyridine-2-sulfuryl guanidine derivative is all very stable in strong acid and weak acid;
2) the pyridine-2-sulfuryl guanidine derivative is stable in organic bases;
3) preparation of pyridine-2-sulfuryl base arginine derivative, raw material is simple, low price;
4) pyridine-2-sulfuryl base just can be realized the protection fully of guanidine radicals;
5) Chang Yong polypeptide method of condensing all can be used in contain the arginic polypeptide of pyridine-2-sulfuryl base synthetic in;
6) pyridine-2-sulfuryl base, can with the most conventional amino protecting group: Boc, Cbz, Fmoc etc. the use of arranging in pairs or groups, also can with the most conventional carboxyl-protecting group: OMe, OBn, OBu-t etc. the use of arranging in pairs or groups.
Embodiment
Below illustrate the preparation of the derivative of pyridine-2-sulfuryl guanidine, these examples just to how preparing this compounds remark additionally, and are not preparation method and such application of compound that limits this compounds.
Embodiment 1 preparation pyridine-2-sulfuryl chlorine
(2.22g, 20mmol) the 2-mercaptopyridine is dissolved in 100mlCH
2Cl
2In the mixed solvent of 100ml 1N hydrochloric acid ,-10～10 ℃, best-5～5 ℃, under the vigorous stirring, slowly drip clorox (3eq), dropwise, temperature is controlled at-10～10 ℃, stirs 30 minutes.Mixed solution is transferred to rapidly in advance in the refrigerative separating funnel, dichloromethane layer, use the cold saturated NaHCO of 50ml respectively
3The saturated common salt washing that solution 50ml is cold.Organic phase is with activatory 4A molecular sieve (perhaps anhydrous Na
2SO
4) in-20～10 ℃ of dry 1h, best-20～0 ℃ of filtrations, concentrating under reduced pressure gets faint yellow oily thing pyridine-2-sulfuryl chlorine (2.2g), productive rate: 72%.
1H?NMR(CDCl3，400MHz)δ：8.84(m，1H，Pyridyl?CH)，8.14-8.05(m，2H，Pyridyl?CH)，7.71(m，1H，Pyridyl?CH)；
13C?NMR(CDCl
3，100MHz)δ：159.2，150.7，139.0，129.0，121.9。
Embodiment 2 preparation Cbz-Arg (Pyr)-OH:
In the three-necked flask of 100ml, add (1.85g, 6mmol) Cbz-Arg, 30ml acetone and 10ml water, be cooled under the magnetic agitation below 0 ℃, regulate pH to 11～11.5, slowly drip Pyr-Cl (2.12g with NaOH, 12mmol) be dissolved in the acetone soln of 10ml, constantly drip 4N NaOH adjusting simultaneously and make reaction solution pH keep 11～11.5, after continuing to stir 1h below 0 ℃, normal temperature is stirring 1h down, with the TLC monitoring, to reacting completely.Regulate pH=7, acetone is removed in decompression, adds 10ml water, water extracted with diethyl ether (3 * 10ml), discard ether, under 0 ℃, water is regulated pH to 3 then, gets light yellow solid, filter dry faint yellow solid Z-Arg (Pyr)-OH (2.4g), the productive rate: 89.2% of getting.
1H?NMR(DMSO-d6，400MHz)δ：8.62(d，1H，J＝4.13，Pyridyl?CH)，7.99(m，1H，PyridylCH)，7.87(d，J＝7.70Hz?1H，Pyridyl?CH)，7.58-7.52(m，2H，Pyridyl?CH+α-NH)，7.39-7.30(m，5H，Ph)，7.21-6.74(br?m，3H，NH-C(N＝H)-NH))，5.04(s，2H，Cbz?CH
2)，3.92(br?m，1H，Arg?α-CH)，3.07(m，2H，Argδ-CH2)，1.70-1.50(br?m，4H，Arg?β-，γ-CH
2)；
13C?NMR(DMSO-d6，100MHz)δ：174.5(CO-OH)，160.6(Pyridyl?CH)，157.6(C＝N)，156.1(Cbz，C＝O)，149.3(Pyridyl?CH)，138.3(Ph)，137.1(Pyridyl?CH)，128.4(Ph)，127.8(Ph)，127.7(Ph)，126.0(Pyridyl?CH)，120.5(Pyridyl?CH)，65.4(BnCH
2)，54.3(Argα-CH
2)，41.3(δ-CH
2)，28.8(β-CH
2)，25.7(γ-CH
2)；
IR(KBr)：v?
max(cm
-1)：3480-3300(br?d，v
OH，v
NH)，2931(s，v
CH?aliphatic)，1704(s，v
CO)；Positive-ion?ESI-MS(m/z)：(M+Na)
+472。
Embodiment 3 preparation Boc-Arg (Pyr)-OH:
In the three-necked flask of 100ml, add (1.65g, 6mmol) Boc-Arg, 30ml acetonitrile and 20ml saturated sodium carbonate solution, magnetic agitation, be cooled to below 0 ℃, (2.12g 12mmol) is dissolved in the acetonitrile solution of 10ml slowly to drip Pyr-Cl, after continuing to stir 1h below 10 ℃, normal temperature stirs 1h down, with the TLC monitoring, to reacting completely.Adjusting pH=7, acetonitrile is removed in decompression, adding 10ml water, the water extracted with diethyl ether (3 * 10ml), discard ether, water is regulated pH to 2～3, gets light yellow solid, filters, dry faint yellow solid Boc-Arg (Pyr)-OH (2.12g), the productive rate: 85.1% of getting.
1H?NMR(DMSO-d6，400MHz)δ：8.60(d，1H，J＝5.20，Pyridyl?CH)，8.00(m，1H，Pyridyl?CH)，7.83(d，J＝7.72Hz?1H，Pyridyl?CH)，7.60-7.50(m，2H，Pyridyl?CH+α-NH)，7.25-6.53(brm，3H，NH-C(N＝H)-NH))，3.82(br?m，1H，Arg?α-CH)，3.05(m，2H，Arg?δ-CH
2)，1.53-1.40(m，4H，Arg?β-，γ-CH
2)，1.36(s，9H，Boc?CH
3×3)；
13C?NMR(CDCl
3，100MHz)δ：174.2(CO-OH)，159.8(Pyridyl?CH)，157.3(C＝N)，154.8(Boc，C＝O)，149.1(Pyridyl?CH)，137.0(Pyridyl?CH)，126.0(Pyridyl?CH)，120.2(Pyridyl?CH)，77.4(BocC)，54.6(α-CH)，40.4(δ-CH
2)，30.1(β-CH
2)，28.2(Boc?CH
3×3)，25.2(γ-CH
2)；
IR(KBr)：v
max(cm
-1)：3500-3200(br，v
OH，v
NH)，2930(s，v
CH，aliphatic)，1702(s，v
CO)；Positive-ion ESI-MS(m/z)：(M+H
+)416，(M+Na
+)438。
The preparation of embodiment 4 Boc-Arg (Pyr)-Phe-OMe
(0.42g, 1mmol) Boc-Arg (Pyr)-OH and (0.12g, 1mmol) HOSu is dissolved in the dry DMF of 5ml, is cooled to 0 ℃ under the magnetic agitation, slowly adds that (0.25g, 1.2mmol) DCC is dissolved in 2ml exsiccant DMF solution, spends the night under the room temperature.Under 0 ℃, in above-mentioned solution, add (0.22g, 1mmol) Phe-OMeHCl, (0.14g, 1.1mmol) DMAP is dissolved in the mixing solutions of 3ml dry DMF, reacts 24h under the room temperature, with the TLC monitoring, to reacting completely.Remove by filter DCU, pressurization concentrates and desolvates, the residue acetic acid ethyl dissolution, and ethyl acetate is used 1N citric acid, 5%Na respectively
2CO
3, water and saturated common salt water washing.Na
2SO
4After the drying, filter, concentrating under reduced pressure desolvate faint yellow solid, through purification by silica gel column chromatography [V (sherwood oil): V (ethyl acetate)=1: 10], white foam shape solid Boc-Arg (Pyr)-Phe-OMe (0.47g), productive rate: 81.6%.
The preparation of embodiment 5 Cbz-Arg (Pyr)-Ala-OH
(4.49g, 10mmol) Cbz-Arg (Pyr)-OH and (3.51g, 15mmol) hexachloroethane is dissolved in the anhydrous tetrahydro furan of 50ml, be cooled to 0 ℃ under the magnetic agitation, (3.93g, 15mmol) triphenylphosphine is dissolved in 20ml exsiccant tetrahydrofuran solution, reaction 1h in slowly adding.Under 0 ℃, be added drop-wise to that (0.89g 10mmol) in the aqueous solution of the sodium bicarbonate of Ala, reacts 1h under the room temperature, with TLC monitoring, to reacting completely.Remove by filter triphenylphosphinc oxide, water is regulated pH to 2～3, separates out faint yellow precipitation, filter faint yellow solid Cbz-Arg (Pyr)-Ala-OH (3.81g), productive rate: 73.3%.
The preparation of embodiment 6 Cbz-Arg (Pyr)-Gly-Asp (OMe)-OMe
(0.45g, 1mmol) Cbz-Arg (Pyr)-OH and (0.15g, 0.14ml; 1.1mmol) the chloroformic acid tert-butyl ester is dissolved in the dry DMF of 5ml, is cooled to 0 ℃ under the magnetic agitation, under the nitrogen protection; behind 0 ℃ of reaction 0.5h; under 0 ℃, in above-mentioned solution, add (0.25g, 1mmol) Gly-Asp (OMe)-OMeHCl and (0.14g; 1.1mmol) DMAP is dissolved in the solution of dry DMF of 3ml; react 24h under the room temperature, with the TLC monitoring, to reacting completely.Concentrating under reduced pressure desolvates, the residue acetic acid ethyl dissolution, and ethyl acetate is used 1N hydrochloric acid, 5%Na respectively
2CO
3, water and saturated common salt water washing.Na
2SO
4After the drying, filter, concentrating under reduced pressure desolvate faint yellow solid, through purification by silica gel column chromatography [V (ethyl acetate): V (methyl alcohol)=10: 1], white foam shape solid Cbz-Arg (Pyr)-Gly-Asp (OMe)-OMe (0.51g), productive rate: 78.6%.
The preparation of embodiment 7 Cbz-Arg-Phe-OMe
(1mmol, 610mg) Cbz-Arg (Pyr)-Phe-OMe is dissolved in the 10ml anhydrous methanol, under the Ar protection, add (15mmol, 360mg) Mg bits, magnetic agitation 10h, TLC follows the tracks of and reacts completely.0 ℃ adds 10ml water stirring 10min, makes magnesium methylate be converted into Mg (OH) fully
2, filtering to get filtrate, concentrating under reduced pressure desolvates, and gets faint yellow solid Cbz-Arg-Phe-OMe (450mg), productive rate: 96%.
Embodiment 8 NH
2-Arg-Gly-Asp-OH
(1mmol, 650mg) Cbz-Arg (Pyr)-Gly-Asp (OMe)-OMe is dissolved in the 10ml anhydrous methanol, under the Ar protection, add (15mmol, 360mg) Mg bits, magnetic agitation 10h, TLC follows the tracks of and reacts completely.0 ℃ of sodium hydroxide solution 10mL that adds 1N, reaction 2～3h removes fully to methyl esters, filtration, filter cake 10ml methanol wash gets filtrate, and filtrate decompression is concentrated into dried, add 50mL methyl alcohol, small amount of hydrochloric acid is filtered, filtrate adds the palladium carbon 50mg of 10% content, feeds hydrogen reaction 10h, the TLC monitoring, react completely, filter concentrating under reduced pressure, crude product water-ethyl alcohol recrystallization obtains product arginyl glycyl aspartic acid tripeptides (0.27g), productive rate: 78%.
Claims (10)
1. pyridine-2-sulfuryl arginine derivative is characterized in that its structural formula is:
X=H wherein, Cbz, Boc, Fmoc; Y=H, Me, Et, Bn, t-Bu.
2. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 1 is characterized in that its route is:
X=H wherein, Cbz, Boc, Fmoc, any organic chain of alkyl; Y=H, Me, Et, Bn, any organic chain of t-Bu.
3. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 2 is characterized in that may further comprise the steps:
1) the 2-mercaptopyridine is dissolved in the organic solvent, stirs, add clorox, stir, get mixed solution;
2) mixed solution is transferred in the separating funnel, got organic layer, concentrating under reduced pressure gets faint yellow oily thing pyridine-2-sulfuryl chlorine;
3) pyridine-2-sulfuryl chlorine and guanidine radicals is exposed arginine derivative reacts in organic solvent and alkali, pyridine-2-sulfuryl arginine derivative.
4. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 3, it is characterized in that in step 1) described organic solvent is selected from methylene dichloride, ethyl acetate, acetonitrile, toluene, a kind of in the acetate, or be selected from methylene dichloride, ethyl acetate, acetonitrile, toluene, the mixed solvent of a kind of and mineral acid in the acetate.
5. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 3 is characterized in that in step 1), and described organic solvent is the mixed solvent of methylene dichloride and hydrochloric acid.
6. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 3 is characterized in that in step 1), and the time of described stirring is 15～40min.
7. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 3 is characterized in that in step 2) in, described separating funnel cools off in advance.
8. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 3 is characterized in that in step 2) in, the temperature of described concentrating under reduced pressure is 10～15 ℃.
9. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 3 is characterized in that in step 3), and described organic solvent is selected from methylene dichloride, ethyl acetate, acetonitrile, tetrahydrofuran (THF), ethanol, acetone, the mixed solvent of a kind of and water in the acetate.
10. the preparation method of pyridine-2-sulfuryl arginine derivative as claimed in claim 3 is characterized in that in step 3), and described alkali is organic bases or mineral alkali.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554039A (en) * | 2013-10-25 | 2014-02-05 | 广西师范大学 | N-2-pyrazine sulfonylated amino acid and synthesis method thereof |
| CN106053426A (en) * | 2016-05-13 | 2016-10-26 | 中国科学院合肥物质科学研究院 | Method for detecting drugs in human body fluids based on surface enhanced Raman spectrum technology |
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2009
- 2009-02-27 CN CNA2009101111640A patent/CN101492415A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554039A (en) * | 2013-10-25 | 2014-02-05 | 广西师范大学 | N-2-pyrazine sulfonylated amino acid and synthesis method thereof |
| CN106053426A (en) * | 2016-05-13 | 2016-10-26 | 中国科学院合肥物质科学研究院 | Method for detecting drugs in human body fluids based on surface enhanced Raman spectrum technology |
| CN106053426B (en) * | 2016-05-13 | 2019-07-19 | 中国科学院合肥物质科学研究院 | Method based on drugs in Surface enhanced Raman spectroscopy technology detection human body fluid |
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