CN1160358C - (8S,18S)-1,4,10,13,16-pentazatricyclo [16.3.0.0 4.8] heneicosane-9,17-diketone and its prepn process - Google Patents
(8S,18S)-1,4,10,13,16-pentazatricyclo [16.3.0.0 4.8] heneicosane-9,17-diketone and its prepn process Download PDFInfo
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- CN1160358C CN1160358C CNB021391475A CN02139147A CN1160358C CN 1160358 C CN1160358 C CN 1160358C CN B021391475 A CNB021391475 A CN B021391475A CN 02139147 A CN02139147 A CN 02139147A CN 1160358 C CN1160358 C CN 1160358C
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Abstract
The present invention discloses novel acylamide type chiral macrocyclic polyamine with C2 symmetry, namely (8S, 18S)-1, 4, 10, 13, 16-pentazatricyclo [16.3.0.0<4, 8>] heneicosane-9, 17-diketone, and a preparation method thereof. The method comprises the steps: L-proline is used as raw materials to prepare the chiral compound, namely the (8S, 18S)-1, 4, 10, 13, 16-pentazatricyclo [16.3.0.0<4, 8>] heneicosane-9, 17-diketone, by esterification, bridging connection and cycle closure. The preparation method dose not need protection of functional radicals, dose not need highly dilution methods, dose not need purification of column chromatography and dose not need special reagents and equipment, and has the characteristics of simple operation, convenient treatment, low cost, etc. Simultaneously, when used as an NMR chiral solvent, the compound shows better identifying effect on compounds in a phenylacetic acid structure with alpha-chiral hydrogen. Thus, the compound can be used for separating and analyzing chiral compounds.
Description
Technical field
The invention discloses a kind of C of having
2Symmetric acid amide type chirality Macrocyclic polyamine (8S, 18S)-1,4,10,13,16-pentaaza three ring [16.3.0.0
4,8] heneicosane-9,17-diketone and its production and use belongs to the preparing technical field of chirality macrocylc compound, also relates to chipal compounds Separation of Enantiomers, analysis field.
Background technology
Supramolecular chemistry is that two or more chemical species are borrowed the entity of intermolecular interaction formation or the chemistry of aggregate, has now become and has developed rapidly, is rich in one of challenging frontier in the chemistry.Supramolecular combination all is based upon on the molecular recognition basis.So-called molecular recognition is exactly main body (or acceptor) to object (or substrate) selective binding and produces the process of certain specific function, is the basis of assembling and assembling function, is the foundation of enzyme and receptor-selective.Because the basic structural unit of a few class biomacromolecules (as nucleic acid, protein and polysaccharide) all is a chipal compounds, great majority other physiologically active substance (as hormone, neurotransmitter etc.) and medicine also all are chiralitys, so chiral recognition becomes the heat subject of supramolecular chemistry research.
People have utilized the chirality macrocylc compound that some chiral molecules (as medicine, neurotransmitter etc.) have been carried out research of molecular recognition.The crown compound of chirality contains organic amine ionic compound to some and has recognition reaction preferably, research to it is comparatively deep, wherein have the separation of the compound of 18 hats, 6 tetracarboxylic acid structures at chiral compound enantiomer, the analysis aspect has obtained practical application.The chirality Macrocyclic polyamine then has recognition reaction preferably to some organic anions, organic neutral molecule, and Macrocyclic polyamine also helps and carry out functionalizing, and is because the synthetic difficulty is bigger, less relatively to its research.
In recent years, some have optically active macrocyclic polyamine compound and are produced out.1.Rugang Xie etc. are raw material with amino acid (Histidine, phenylalanine, leucine, Isoleucine, L-Ala), have synthesized the chirality Macrocyclic polyamine that contains pyridine ring.(Syn.Commun.，1999，29，2447-2455)。2.Janusz Jurczak etc. are that raw material has synthesized and has C with the L-proline(Pro)
2And C
3Symmetric Macrocyclic polyamine (Tetrahedron:Asymmetry, 2001,12,111-119; Tetrahedron:Asymmetry, 2001,12,487-495).3.Picard Deng with (R, R)-tartrate be ring closure reaction that raw material passes through 2+2 synthesized one group of symmetric and asymmetric macrocyclic amide (Tetrahedron, 1997,53,13757-13768).4.Vicente the adjacent diamino-cyclohexane of usefulness such as Gotor is a raw material has synthesized and has had C
2And D
2The big ring of symmetric dioxy four azepine chiralitys (Chem.Eur.J., 2000,6,3331-3338).5.Cynthia J.Burrows etc. with amino acid (phenylalanine, leucine, Xie Ansuan) be the raw material big ring of the dioxy Cyclan that synthesized chirality (J.Org.Chem., 1989,54,1584-1589).6.Wolfgang Beck etc. utilize metal ion for template inactive dipeptides ester to be synthesized 12-, 14-, and 16-, the cyclic tetrapeptide of 18-unit (encircling four acid amides greatly) (Angew Chem.Int.Ed.Enl., 1998,37,1086-1089).
In many preparations, method 3 needs to adopt highly dilution method, and the productive rate of method 1,5 is lower, less than 10%, and method 2,3,4 productive rate is higher, but method 1,2,3,4,5 needs to carry out purifying with column chromatography in preparation process.The productive rate of method 6 is also higher, but needs to adopt metal ion as template and special reagent.And what make in the method 2 has a C
2Symmetric chiral molecules is when carrying out molecular recognition to a pair of enantiomorph, and it is disadvantageous to molecular recognition that the top and bottom of ring system have different chemical environments.
Summary of the invention
It is simple that problem solved by the invention provides a kind of preparation, and with low cost have a C
2Symmetric acid amide type chirality Macrocyclic polyamine (8S, 18S)-1,4,10,13,16-pentaaza three ring [16.3.0.0
4,8] heneicosane-9,17-diketone and its production and use.
Technical scheme provided by the invention is: have C
2Symmetric acid amide type chirality Macrocyclic polyamine (8S, 18S)-1,4,10,13,16-pentaaza three ring [16.3.0.0
4,8] heneicosane-9, the 17-diketone, its molecular formula is C
16H
29N
5O
2, structural formula is
Above-mentioned have a C
2Symmetric acid amide type chirality Macrocyclic polyamine (8S, 18S)-1,4,10,13,16-pentaaza three ring [16.3.0.0
4,8] heneicosane-9; the preparation method of 17-diketone: with 1; 2-two [2-methoxycarbonyl-1-pyrrolidyl] ethane (1; 2-Bis[2-carbomethoxy-1-pyrrolidinyl] ethane; its method for making reference Inorganic Chemistry Vol.14; No.10,1975,2347) at airbath 30-80 ℃; react with diethylenetriamine in methyl alcohol or the ethanolic soln under the nitrogen protection condition; solvent evaporated after finishing, promptly have a large amount of (8S, 18S)-1; 4; 10,13,16-pentaaza three ring [16.3.0.
4,8] heneicosane-9, the 17-diketone is separated out.
The L-proline(Pro) is dissolved in the alcoholic solution, under cryosel bath condition, drips 1.1-1.5 doubly to the SOCl of L-proline(Pro)
2, carry out esterification, desalination acid is then reacted under excessive salt of wormwood or the yellow soda ash effect in acetonitrile solution with glycol dibromide again, suction filtration after reaction is finished, underpressure distillation steams intermediate product 1,2-two [2-methoxycarbonyl-1-pyrrolidyl] ethane.
In aforesaid method, the present invention at first carries out esterification with the L-proline(Pro), and desalination acid is then carried out bridging with glycol dibromide again, and last and diethylenetriamine is closed ring.
Below be the reaction mechanism of preparation compound of the present invention:
Natural amino acid optical purity height, cheap and easy to get, wherein the L-proline(Pro) is uniquely in the natural amino acid to have a five-ring, the amino acid of imino-structure, mono-substituted product can only be obtained with the glycol dibromide reaction, production of by-products can be reduced, can increase the rigidity of ring again, thus we to select the L-proline(Pro) for use be raw material.When a pair of enantiomorph was carried out molecular recognition, it was favourable to molecular recognition that the top and bottom of ring system have identical chemical environment.Just be based on above consideration, we have designed target compound, and (8S, 18S)-1,4,10,13,16-pentaaza three encircles [16.3.0.0
4,8] heneicosane-9, the 17-diketone.This novel C that has disclosed in this invention
2Symmetric acid amide type chirality Macrocyclic polyamine shows recognition effect preferably when the compound of toluylic acid structure with alpha-chiral hydrogen is carried out enantiomorph identification.Therefore, this compound can be used for separation, the analysis of chipal compounds.
This novel acid amide type Macrocyclic polyamine of the present invention's preparation has following characteristics:
1. this compound has the dual-use function of oligopeptides and Macrocyclic polyamine concurrently.Has C
2Symmetry can produce two anchor rings that chemical environment is identical during to the identification of chiral molecules.The imino-on acid amides, have only an imino-, realize selectivity function baseization easily imino-.The rigidity of compound is stronger, is difficult for distortion, is favourable for the identification of chiral molecules.
3. this compound has amphipathicly, is suitable for using in more solvent system.
4. carry out esterification according to method L-proline(Pro) of the present invention, or the ethyl ester effect is identical.
5. can be according to method desalination acid of the present invention at methyl alcohol, ethanol, chloroform carries out in the acetonitrile solution.
6. can use excessive salt of wormwood according to method bridging process of the present invention, or yellow soda ash.
According to method compound of the present invention in the process of preparation not the method for demand pole chromatography carry out purifying, need not adopt highly dilution method, do not need or not use special reagent and equipment, and productive rate to be higher with functional group protection.
8. simple to operate, it is convenient, with low cost to handle.
Embodiment
Bathe under the magneton stirring at cryosel, in 250ml exsiccant flask, add 23.0 gram (0.2mol) L-proline(Pro) and 150ml methyl alcohol, in 30min, drip 16.0ml (0.22mol) SOCl
2, dropwise, react 90min again, reaction 4 hours under 50 ℃ of conditions of airbath then, the pressure reducing and steaming solvent obtains oily mater, adds 50ml methyl alcohol, evaporate to dryness then, triplicate is removed unreacted SOCl as far as possible
2With the HCl gas that produces, place the refrigerator freeze overnight after, obtain block white water absorbability solid 32.4 grams, productive rate＞99%.Under water bath condition, add in the chloroformic solution of above-mentioned product after 12.0 gram (0.3mol) solid NaOH stir 30min, add anhydrous magnesium sulfate drying, continue to stir 60min, filtration under diminished pressure then, solvent evaporated obtains the oily resistates.It is dissolved in the dry acetonitrile of 300ml, adds 17.28 gram (0.095mol) glycol dibromides and 40 gram (0.3mol) Anhydrous potassium carbonates, nitrogen protection is heated to 80 ℃ of reactions 20 hours.Suction filtration elimination insoluble solids obtains flaxen solution, and the evaporated under reduced pressure solvent obtains the yellow oily resistates.The oil pump underpressure distillation is collected the fraction 14.77g (literature value: 136-137 ℃ (1mmHg)) of 180-183 ℃ (10mmHg) (not proofreading and correct), productive rate 55%.It is dissolved in the 350ml anhydrous methanol, add 5.36 gram (0.052mol) diethylenetriamine, under 50 ℃ of conditions of airbath, nitrogen protection, stirring reaction 10 days, evaporate to dryness methyl alcohol is separated out a large amount of white solids, suction filtration, use the acetonitrile recrystallization, get white needle-like crystals 5.04 grams, productive rate 30%, m.p.:278-280 ℃; [α]
D 30=-229.3 (c=1.0, MeOH); MS (FAB) m/z (%): 324 (M
++ 1,100); Ultimate analysis: C
16H
29N
5O
2, theoretical value (%): C, 59.42, N, 21.65, H, 9.04; Measured value (%): C, 59.08, N, 21.03, H, 9.72;
1HNMR (CDCl
3, TMS): δ=7.66 (b, 2H; 2CONH), 3.60-3.75 (m, 2H; 2CHHNHCO), 3.11-3.17 (t, 2H; NCHCO), and 3.02-3.08 (m, 4H, 2CHHNHCO, 2NHCHH), 2.83-2.92 (m, 3H; 2NHCHH, CH
2NHCH
2), 2.70-2.82 (m, 2H; 2NCHH), 2.48-2.61 (m, 2H; 2NCHH), 2.13-2.28 (m, 4H; 2NCH
2), 1.68-1.90 (m, 8H; 4CH
2); IR (KBr, cm
-1): ν=3437.0,3291.0,2957.1,2925.9,2903.7,2853.6,2808.5,1651.6,1523.7,1450.0.
Claims (4)
1. one kind has C
2Symmetric acid amide type chirality Macrocyclic polyamine (8S, 18S)-1,4,10,13,16-pentaaza three ring [16.3.0.0
4,8] heneicosane-9, the 17-diketone, its molecular formula is C
16H
29N
5O
2, structural formula is:
Claim 1 described (8S, 18S)-1,4,10,13,16-pentaaza three ring [16.3.0.0
4,8] heneicosane-9; the preparation method of 17-diketone is characterized in that: with 1,2-two [2-methoxycarbonyl-1-pyrrolidyl] ethane is at airbath 30-80 ℃; react with diethylenetriamine in methyl alcohol or the ethanolic soln under the nitrogen protection condition; solvent evaporated after finishing, promptly have a large amount of (8S, 18S)-1; 4; 10,13,16-pentaaza three ring [16.3.0.0
4,8] heneicosane-9, the 17-diketone is separated out.
3. method according to claim 2 is characterized in that: the L-proline(Pro) is dissolved in the alcoholic solution, drips 1.1-1.5 doubly to the SOCl of L-proline(Pro) under cryosel bath condition
2, carry out esterification, desalination acid is then reacted under excessive salt of wormwood or the yellow soda ash effect in acetonitrile solution with glycol dibromide again, suction filtration after reaction is finished, underpressure distillation steams intermediate product 1,2-two [2-methoxycarbonyl-1-pyrrolidyl] ethane.
Claim 1 described (8S, 18S)-1,4,10,13,16-pentaaza three ring [16.3.0.0
4,8] heneicosane-9, the 17-diketone is used for separation, the analysis of chipal compounds.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021391475A CN1160358C (en) | 2002-10-09 | 2002-10-09 | (8S,18S)-1,4,10,13,16-pentazatricyclo [16.3.0.0 4.8] heneicosane-9,17-diketone and its prepn process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021391475A CN1160358C (en) | 2002-10-09 | 2002-10-09 | (8S,18S)-1,4,10,13,16-pentazatricyclo [16.3.0.0 4.8] heneicosane-9,17-diketone and its prepn process |
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| CN1403458A CN1403458A (en) | 2003-03-19 |
| CN1160358C true CN1160358C (en) | 2004-08-04 |
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| CN1296360C (en) * | 2004-12-15 | 2007-01-24 | 武汉大学 | (1R,2R) or (1S,2S)-1-(4'-substitute-1'8'-naphthoyl imdo group)-2-amino cyclohexane, preparation and application |
| TWI577665B (en) * | 2010-02-11 | 2017-04-11 | 必治妥美雅史谷比公司 | Macrocycles as factor xia inhibitors |
| CN102766005B (en) * | 2012-08-01 | 2014-02-19 | 福州大学 | Chiral compound separation method based on nano gold modified by aptamer |
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