CN102718768A - Chiral five-membered bicyclic guanidine compound, preparation method and application thereof - Google Patents
Chiral five-membered bicyclic guanidine compound, preparation method and application thereof Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a chiral five-membered bicyclic guanidine compound, a preparation method and an application thereof. The chiral five-membered bicyclic guanidine compound is shown as Formula (I). The preparation method can be obtained by referring to existing synthetic routes of the chiral five-membered bicyclic guanidine compound and performing proper changes. The two side chains of the chiral five-membered bicyclic guanidine compound are diphenylmethyl, so that a larger chiral space is formed. Moreover, phenyl may form Pi-Pi overlap with a substrate containing conjugated groups so as to improve the effects of chiral induction. Therefore, more substrates as catalysts can be applied to the compound of Formula (I), and the chiral five-membered bicyclic guanidine compound of the invention is better than the existing chiral five-membered bicyclic guanidine compound as for catalytic performance.
Description
Technical field
The present invention relates to the synthetic field of compound, be specifically related to a kind of chirality five-membered two ring guanidine compounds.
Background technology
Guanidine is a kind of organic alkali, has had the asymmetric reaction that the report guanidine compound can a series of base catalysis of catalysis (to see document Ishikawa, T.; Isobe, T. Chem. Eur. J. 2002,8,553 ~ 557), the for example not Strecker reaction etc. of alkali of the silation of epoxidation reaction, addition reaction, secondary alcohol and west.2008; The research group of Tan develops a kind of chirality five-membered two ring guanidine compounds 1; It has been proved to be a kind of effective organic micromolecule catalyst, can the catalysis Michael addition, Manny is western, protonated etc., and reaction (is seen document Advanced Synthesis and Catalysis, 2007; 349,2454 ~ 2458; Chem. Eur. J. 2011,17, and 3571 ~ 3574; Chem. Eur. J. 2010,16, and 779 ~ 782; Angew. Chem. Int. Ed. 2008,47,5641 ~ 5645).
Although this compound 1 can a plurality of reactions of catalysis, its catalytic reaction substrate certain limitation is arranged.The substrate that usually can react for a certain class can only be finely tuned its structure, and too big modification can cause the low even reaction of reaction yield to carry out.Therefore, the Application of Catalyst that has compound 1 structure has received bigger restriction.Mostly picture is the compound of some ring texturees at present about the catalysis report of compound 1, like annulenones, cyclic lactone, cyclic lactam and maleimide, and for the compound of some linear structures, less about its catalysis report.
Therefore developing the better guanidine compound of a kind of catalytic performance has practical significance.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, a kind of novel chirality five-membered two ring guanidine compounds are provided, this compound has the performance of better catalysis asymmetric reaction.
Another object of the present invention is to provide the preparation method of said chirality five-membered two ring guanidines.
Another object of the present invention is to provide the application of said chirality five-membered two ring guanidines.
Above-mentioned purpose of the present invention is achieved through following technical scheme:
A kind of chirality five-membered two ring guanidine compounds, said chirality five-membered two ring guanidine compounds have structure shown in the formula I:
（Ⅰ）
Through contriver's analysis, the limitation of chirality five-membered two ring guanidine compounds, 1 catalytic substrate of prior art possibly come from following two reasons: 1) side chain of this compound only is the tertiary butyl, its chiral induction space that can form less; 2) can not form π-π additive effect between the substrate of the tertiary butyl and band conjugation group, reduce the reactive force of chiral induction.
Two side chains of formula I compound are diphenyl-methyls; Chirality space than the tertiary butyl forms is bigger, and simultaneously, phenyl might form π-π additive effect with the substrate of band conjugation group; Increase the effect of chiral induction; Therefore, the catalytic substrate of formula I compound is wider, has than existing chirality five-membered two ring guanidine compounds, 1 better catalytic performance.
The preparation method of said chirality five-membered two ring guanidine compounds, synthetic route that can reference compound 1 is carried out suitable adjustment again.
As a kind of preferred version, the preparation method of said chirality five-membered two ring guanidine compounds comprises the steps:
(1) is starting raw material with amino alcohol 3, under the catalysis of trifluoromethane sulfonic acid, reacts, obtain amino alcohol 4 with benzene;
(2) adopt tosylation to protect to the amino on the amino alcohol 4, obtain compound 5, in the presence of triethylamine, Dimethylamino pyridine and methylsulfonyl chloride, carry out cyclisation again, cross post and separate, obtain ethylenimine 6 pure article;
(3) ethylenimine 6 carries out ring-opening reaction in the presence of ammonia, obtains primary amine 7; Primary amine 7 reacts with ethylenimine 6 again, after reaction finishes, crosses post and separates the compound 8 pure article that obtain;
(4) compound 8 is carried out protective reaction, slough its p-toluenesulfonyl, obtain triamine 9;
(5) triamine 9 is dissolved in the Nitromethane 99Min., after trithiocarbonic acid dimethyl ester back flow reaction, has the refluxed reaction at acetate and methyl iodide again, and the reaction back is removed and desolvated, and crosses post and obtains iodate hydrogen salt 10;
(6) iodate hydrogen salt 10 is dissolved in the methylene dichloride, in the presence of salt of wormwood, reacts, and obtains the said chirality five-membered two ring guanidine compounds of formula I;
As a kind of preferred version, step (1) is preferably carried out as follows: in flask, add benzene and trifluoromethane sulfonic acid, add amino alcohol 3 then, stirring reaction number hour.After reaction finishes, place ice to cool off reaction solution, adopt sodium hydroxide that it is neutralized then, adopt chloroform that product is extracted.The organic phase of gained is water and saturated common salt water washing successively, uses dried over mgso at last, filters, and removal of solvent under reduced pressure obtains amino alcohol 4 bullions.The transformation efficiency and the purity of this step reaction are all higher, so amino alcohol 4 bullions can directly be used for next step reaction.
As a kind of preferred version, step (2) is preferably carried out as follows: adopt tosylation to protect to the amino on the amino alcohol 4, obtain compound 5 after; Bullion kind toward compound 5 adds triethylamine and Dimethylamino pyridine, and adopting the exsiccant methylene dichloride is solvent, in ice bath, stirs; Slowly add methylsulfonyl chloride, at room temperature stirred 3 hours, add entry then; And the pH value of reaction system is transferred to 2 with concentrated hydrochloric acid, stir separatory.Adopt methylene dichloride to extract again, after gained organic phase water and the saturated common salt water washing, use anhydrous sodium sulfate drying,, obtain ethylenimine 6 bullions except that after desolvating.Bullion passed through post again to be separated, and obtains the ethylenimine 6 pure article of white solid.
As a kind of preferred version, in the step (3), being reflected under the exsiccant acetonitrile of the generation compound 8 of preferred ethylenimine 6 and primary amine 7, backflow is carried out.
As a kind of preferred version, in the reaction of the generation compound 8 of step (3) ethylenimine 6 and primary amine 7, preferred ethylenimine 6 feeds intake with the mol ratio of primary amine 7 by 1.2:1.
As a kind of preferred version, step (3) is preferably carried out as follows: ethylenimine 6 pure article are dissolved in the methyl alcohol, under 0 ℃, blast ammonia 30 minutes; The sealed reaction bottle slowly rises to room temperature and protects stirred overnight with the ammonia ball subsequently; Remove and desolvate, promptly obtain primary amine 7, in primary amine 7; Adding is with respect to primary amine 71.2 normal ethylenimine 6 pure article and be dissolved in the dry acetonitrile, is heated to more than 95 ℃ to reflux, after reaction finishes; Remove and desolvate, cross post and separate the compound 8 pure article that obtain.
The protective reaction of compound 8 can carry out with reference to the tolysulfonyl radical reaction that takes off of routine.As a kind of preferred version, step (4) is preferably carried out as follows: in flask, add sodium, be cooled to-78 ℃, feed ammonia, make ammonia be condensed into liquid, stir, form navy blue liquid.With THF dissolved compound 8, join in the above-mentioned mazarine liquid, sealing was stirred 4 hours, if between the reaction period, mazarine is taken off, and then adds sodium.After reaction was accomplished, uncap was warming up to room temperature naturally, stirred to add chloride solid down, until forming white mixture.Add methylene dichloride at last, stir, filter, the solid with washed with dichloromethane obtains removes and desolvates, and obtains triamine 9.The purity of triamine 9 is higher, can directly carry out next step reaction.
As a kind of preferred version, step (5) is preferably carried out as follows: triamine 9 is dissolved in the Nitromethane 99Min., after trithiocarbonic acid dimethyl ester back flow reaction; Be cooled to room temperature, have the refluxed reaction at acetate and methyl iodide again, be cooled to stirred overnight after the room temperature; Add dichloromethane extraction,, adopt methylene dichloride that crude product is dissolved except that after desolvating; Select for use the eluent of methylene dichloride and methyl alcohol volume ratio 19:1 to carry out post again and separate, obtain iodate hydrogen salt 10.
As a kind of preferred version; Step (6) is preferably carried out as follows: iodate hydrogen salt 10 is dissolved in the methylene dichloride, in the presence of salt of wormwood, reacts, and filters then; Collect filtrating; And remove and desolvate, obtain faint yellow oily thing, i.e. the said chirality five-membered two ring guanidine compounds of formula I.
The chirality five-membered two ring guanidine compounds of said formula I have good catalytic performance for asymmetric reaction, can be used as the catalyzer of asymmetric reaction in synthetic.
Compared with prior art, the present invention has following beneficial effect:
Chirality five-membered two ring guanidine compounds according to the invention have novel structure, and it is compared with existing chirality five-membered two ring guanidine compounds, has better asymmetric reaction catalytic performance, has the better application prospect.
Embodiment
Below in conjunction with specific embodiment the present invention is further explained, but specific embodiment is not done any qualification to the present invention.
Embodiment 1The preparation of the chirality five-membered two ring guanidine compounds of formula I
(1) in flask, add benzene (5.0 milliliters) and trifluoromethane sulfonic acid (20.0 milliliters), add
Amino alcohol 3(1.0 gram) stirred 3 ~ 6 hours.Reaction solution is poured in about 100 gram ice, fully stirs, with in the sodium hydroxide solution and after, use chloroform extraction.Organic phase is water and saturated common salt water washing successively, uses dried over mgso at last, filters, and removal of solvent under reduced pressure obtains
Amino alcohol 4Bullion (1.29 gram, 96% productive rate).This bullion can directly be used for next step reaction.
(2) in flask, add
Amino alcohol 4(1 gram), triethylamine (2.1 milliliters) and exsiccant acetonitrile (11 milliliters) are cooled to 0 ~ 5 ℃ in the ice bath stirring.Add Tosyl chloride (0.8 gram), in ice bath, stir half a hour, be warming up to room temperature naturally, restir 2 ~ 4 hours is until reacting completely.After the removal of solvent under reduced pressure, add ETHYLE ACETATE (20 milliliters), filter, use the ETHYLE ACETATE wash solids.The evaporation of gained filtrating except that desolvating, is obtained
Compound 5Bullion.Toward being somebody's turn to do
Compound 5In the bullion, add triethylamine (2.1 milliliters) and Dimethylamino pyridine (0.46g), add exsiccant methylene dichloride (11 milliliters), in ice bath, stir, slowly add methylsulfonyl chloride (0.57 milliliter), at room temperature stirred then 3 hours.Add 10 ml waters, pH is transferred to 2, stir separatory with concentrated hydrochloric acid.Use methylene dichloride (10 milliliters, 5 milliliters) aqueous phase extracted again, separatory.Merge organic phase, anhydrous sodium sulfate drying is used in water and saturated common salt water washing, and removal of solvent under reduced pressure obtains
Ethylenimine 6Bullion.Separate through column chromatography, obtain white solid
Ethylenimine 6(1.28 grams, from
Amino alcohol 4Arrive
Ethylenimine 6Overall yield 80%).
(3)
Ethylenimine 6(1 gram) is dissolved in 20 ml methanol, under 0 ℃, blasts ammonia 30 min, and the sealed reaction bottle slowly is warming up to room temperature and also protects with the ammonia ball subsequently.Stirred overnight, vacuum rotary steam are removed to desolvate and are obtained yellow oil, for
Primary amine 7Bullion.In this bullion, add in addition
Ethylenimine 6(1.2 gram) is dissolved in exsiccant acetonitrile (10 ml), is heated to 95 ℃ of back flow reaction.After reaction finished, removal of solvent under reduced pressure was crossed the post separation and is obtained
Compound 8(from 6 to 8 yields are 82% for white solid, 1.68 grams).
(4) in flask, add sodium, be cooled to-78 ℃, feed ammonia, make ammonia be condensed into liquid (about 50 milliliters), stir, form navy blue liquid, if can't form navy blue liquid, perhaps blueness is taken off, and adds sodium and forms until mazarine liquid.Dissolve with THF (5 milliliters)
Compound 8(1 gram) joins in the above-mentioned dark blue solution, stirs 4 hours.During this time, if mazarine is taken off, then add sodium.After 4 hours, uncap is warming up to room temperature naturally, stirs to add chloride solid down, until forming white mixture.Add methylene dichloride (25 milliliters), stirred 0.5 hour, filter, use the washed with dichloromethane solid.Merging filtrate, removal of solvent under reduced pressure obtains
Triamine 9Bullion (yellow oil), can directly be used for next step reaction.
(5) get above
Triamine 9(113 mg, 0.26 mmol) is dissolved in the Nitromethane 99Min. (1 ml), slowly drips Nitromethane 99Min. solution (the 36 μ l of trithiocarbonic acid dimethyl ester; 0.33 dissolving of mmol trithiocarbonic acid dimethyl ester and 0.1mL Nitromethane 99Min.); Be heated to 110 ℃, refluxed 2 hours, cold cut is to room temperature.Add acetate (61 μ l, 1.06 mmol) and methyl iodide (49 μ l, 0.53 mmol), at 110 ℃, 3 h that reflux are cooled to stirred overnight under the room temperature.Add methylene dichloride (1 ml) vacuum rotary steam except that desolvating, (1 ml) dissolving that adds methylene chloride is again crossed post with methylene dichloride and methyl alcohol (19:1) and is separated, and obtains
Iodate hydrogen salt 10(about 100mg, 67.3% productive rate).
(6) with the iodate hydrogen salt
10(100mg) be dissolved in the methylene dichloride (2mL), add salt of wormwood (0.5 gram), stirred 0.5 hour, filter, the solvent of gained filtrating is removed in decompression, obtains faint yellow oily thing, is
The said chirality five-membered two ring guanidine compounds of formula I(63mg, yield 81%).
Hydrogen spectrum, carbon spectrum and the mass-spectrometric data of the said chirality five-membered two ring guanidine compounds of formula I are following: 1H NMR (500 MHz, CDCl
3, ppm):
δ7.10-7.24 (m, 20H), 4.35 (d, 2H), 3.55 (m, 2H), 2.85 (dd,
J=5.2,8.7 Hz, 2H), 3.05 (dd,
J=6.8,8.7 Hz, 2H).
13C NMR (500 MHz, CDCl
3, ppm):
δ55.0,68.2,48.4,144.0,129.1,129.2,126.2, mass spectrum m/z 444.32 (M+H
+).
Embodiment 2 catalysis experiment
Below, we provide the formula I compound to be applied to the embodiment of the Michael reaction of catalysis 2-cyclopentenone and methyl-malonate.
2-cyclopentenone (0.025 mmole) and methyl-malonate (0.03 mmole, 1.2 equivalents) are dissolved in (0.1 milliliter) in the toluene, stirring at room.The said compound catalyst of formula I (1.1 milligrams, 0.0025 mmole, 0.01 equivalent) is dissolved in 0.01 milliliter of toluene, joins in the reactant, stir, monitor reaction process with thin-layer chromatography.After 6 days, stopped reaction is crossed the post separating prod in stirring at room
12(2.94 milligrams, 55% productive rate).
In order to detect
Product (S)-(-)-12Chiral purity, can this product be changed into
Acetal (S)-13After, with chiral column stratographic analysis chiral purity.Condition is: CHIRALCEL OD-H (4.6 mm i.d. x, 250 mm), normal hexane/Virahol=97/3, flow velocity 0.5 ml/min; 25 ℃; 210 nm; RT: 25.0 minutes (secondary peaks) and 26.2 min (main peaks).Analytical results shows that main peaks ee value is 45%.
Show that more than the formula I compound has the effect of asymmetry catalysis.
Embodiment 3 catalytic performance comparative experimentss
The rare Michael reaction with methyl-malonate of oil of mirbane second is widely used in chiral molecules synthetic.
Different with this cyclic substrate of 2-cyclopentenone of embodiment 2, a kind of in fact oil of mirbane second is rare to be a kind of linear substrate.Yet, because
Compound 1Catalytic performance or catalytic condition be restricted, employing is not arranged at present as yet
Compound 1The report of the rare Michael reaction with methyl-malonate of success catalysis oil of mirbane second.We are catalyzer with the formula I compound, have carried out following experiment:
Oil of mirbane second rare (0.025 mmole) and methyl-malonate (0.03 mmole, 1.2 equivalents) are dissolved in (0.1 milliliter) in the toluene, stirring at room.The said compound catalyst of formula I (1.1 milligrams, 0.0025 mmole, 0.01 equivalent) is dissolved in 0.01 milliliter of toluene, joins in the reactant, stir, monitor reaction process with thin-layer chromatography.After 3 days, stopped reaction is crossed the post separating prod in stirring at room
12(5.27 milligrams, 75% productive rate).
In order to detect
Product 14Chiral purity, with chiral column stratographic analysis chiral purity.Condition is: CHIRALCEL AD, and normal hexane/Virahol=90/10,1ml/min, 210nm, 15.3min (main peak), 11.8min (secondary peak), analytical results shows that the ee value is 32%.
Show that more than the formula I compound has the effect of asymmetry catalysis, both has been applicable to the cyclic substrate like the 2-cyclopentenone, also is used in the linear substrate like rare type of oil of mirbane second.More tentatively can find out from above-mentioned; Formula I compound of the present invention is compared with existing compound 1; The catalytic substrate kind is more, and its potential using value is wider, along with going deep into of research; The formula I compound can carry out the reaction of more base catalysis, and this compound can obtain to use widely.
Claims (6)
1. chirality five-membered two ring guanidine compounds is characterized in that, said chirality five-membered two ring guanidine compounds have structure shown in the formula I:
（Ⅰ）。
2. the preparation method of the said chirality five-membered two ring guanidine compounds of claim 1 is characterized in that, comprises the steps:
(1) is starting raw material with amino alcohol 3, under the catalysis of trifluoromethane sulfonic acid, reacts, obtain amino alcohol 4 with benzene;
(2) adopt tosylation to protect to the amino on the amino alcohol 4, obtain compound 5, in the presence of triethylamine, Dimethylamino pyridine and methylsulfonyl chloride, carry out cyclisation again, cross post and separate, obtain ethylenimine 6 pure article;
(3) ethylenimine 6 carries out ring-opening reaction in the presence of ammonia, obtains primary amine 7; Primary amine 7 reacts with ethylenimine 6 again, after reaction finishes, crosses post and separates the compound 8 pure article that obtain;
(4) compound 8 is carried out protective reaction, slough its p-toluenesulfonyl, obtain triamine 9;
(5) triamine 9 is dissolved in the Nitromethane 99Min., after trithiocarbonic acid dimethyl ester back flow reaction, has the refluxed reaction at acetate and methyl iodide again, and the reaction back is removed and desolvated, and crosses post and obtains iodate hydrogen salt 10;
(6) iodate hydrogen salt 10 is dissolved in the methylene dichloride, in the presence of salt of wormwood, reacts, and obtains the said chirality five-membered two ring guanidine compounds of formula I;
3. preparation method as claimed in claim 2 is characterized in that, in the step (3), and being reflected under the exsiccant acetonitrile of the generation compound 8 of ethylenimine 6 and primary amine 7, backflow is carried out.
4. preparation method as claimed in claim 2 is characterized in that, in the reaction of the generation compound 8 of step (3) ethylenimine 6 and primary amine 7, ethylenimine 6 feeds intake with the mol ratio of primary amine 7 by 1.2:1.
5. preparation method as claimed in claim 2 is characterized in that, in the step (5), crosses post and selects for use the eluent of methylene dichloride and methyl alcohol volume ratio 19:1 to carry out.
6. said chirality five-membered two application of ring guanidine compound in asymmetric catalysis of claim 1.
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| WO2014000455A1 (en) * | 2012-06-26 | 2014-01-03 | 惠州市莱佛士制药技术有限公司 | Chiral five-membered bicyclic guanidine compound, and preparation method and application thereof |
| CN103044434A (en) * | 2012-12-17 | 2013-04-17 | 惠州市莱佛士制药技术有限公司 | Preparation method for chiral pentabasic bicyclic guanidine based on aziridine |
| CN103272638A (en) * | 2013-06-04 | 2013-09-04 | 大连理工大学 | Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof |
| CN103272638B (en) * | 2013-06-04 | 2015-04-22 | 大连理工大学 | Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof |
| CN103664959A (en) * | 2013-12-12 | 2014-03-26 | 惠州市莱佛士制药技术有限公司 | Preparation method of five-membered bicyclic guanidine compounds |
| CN104592253A (en) * | 2014-12-29 | 2015-05-06 | 惠州市莱佛士制药技术有限公司 | New synthesis method for temsirolimus |
| CN104592253B (en) * | 2014-12-29 | 2020-01-17 | 广东莱佛士制药技术有限公司 | Novel synthesis method of temsirolimus |
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| Publication number | Publication date |
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| CN102718768B (en) | 2014-10-08 |
| WO2014000455A1 (en) | 2014-01-03 |
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