CN117700368A - Synthesis method of pentanitrogen guanidine salt chiral phase transfer catalyst - Google Patents
Synthesis method of pentanitrogen guanidine salt chiral phase transfer catalyst Download PDFInfo
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- CN117700368A CN117700368A CN202311705763.1A CN202311705763A CN117700368A CN 117700368 A CN117700368 A CN 117700368A CN 202311705763 A CN202311705763 A CN 202311705763A CN 117700368 A CN117700368 A CN 117700368A
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- -1 pentanitrogen guanidine salt Chemical compound 0.000 title claims abstract description 60
- 239000003444 phase transfer catalyst Substances 0.000 title claims abstract description 56
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 57
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 19
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 16
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims abstract description 14
- PONXTPCRRASWKW-UHFFFAOYSA-N 1,2-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1C(N)C(N)C1=CC=CC=C1 PONXTPCRRASWKW-UHFFFAOYSA-N 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims abstract description 6
- PFRDRCIPKPEULG-UHFFFAOYSA-N imidazol-2-imine Chemical class N=C1N=CC=N1 PFRDRCIPKPEULG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000376 reactant Substances 0.000 claims abstract description 6
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims abstract description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000012046 mixed solvent Substances 0.000 claims abstract description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000010898 silica gel chromatography Methods 0.000 claims description 11
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims description 8
- NBRNHHKYVFAXCZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=CC=C1CBr NBRNHHKYVFAXCZ-UHFFFAOYSA-N 0.000 claims description 3
- QGXNHCXKWFNKCG-UHFFFAOYSA-N 2-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC=C1C#N QGXNHCXKWFNKCG-UHFFFAOYSA-N 0.000 claims description 3
- DISXFZWKRTZTRI-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-2-amine Chemical class NC1=NCCN1 DISXFZWKRTZTRI-UHFFFAOYSA-N 0.000 claims description 3
- HWKRYMGLNZFYCG-UHFFFAOYSA-N 4-(bromomethyl)-3-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC(C#N)=CC=C1CBr HWKRYMGLNZFYCG-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- ATLQGZVLWOURFU-UHFFFAOYSA-N 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(CBr)=CC(C(F)(F)F)=C1 ATLQGZVLWOURFU-UHFFFAOYSA-N 0.000 claims description 2
- CHCAGFNTASDQFX-UHFFFAOYSA-N 2-(bromomethyl)-4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C(CBr)=C1 CHCAGFNTASDQFX-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 6
- 238000010189 synthetic method Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000004458 analytical method Methods 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 8
- 238000010183 spectrum analysis Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 150000004693 imidazolium salts Chemical class 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a pentanitrogen guanidine salt chiral phase transfer catalyst, which comprises the following steps of S1, taking chiral 1, 2-diphenyl-1, 2-ethylenediamine and cyanogen bromide as reactants, and heating in acetonitrile solvent to react to obtain chiral 2-imine imidazolinium salt; s2, chiral 1, 2-diphenyl-1, 2-ethylenediamine and 3, 5-di-tert-butyl bromobenzyl are taken as reactants to react in acetonitrile solvent to obtain chiral secondary amine; s3, reacting the chiral secondary amine with thiophosgene in a mixed solvent of dichloromethane and water to obtain chiral thiourea; s4, dissolving chiral thiourea in toluene, adding oxalyl chloride, and heating for reaction to obtain an intermediate; the intermediate reacts with chiral 2-iminoimidazolium salt in acetonitrile at the temperature of 70-90 ℃ to prepare pentanitrogen guanidine salt intermediate NH-PN, and then the pentanitrogen guanidine salt intermediate NH-PN further reacts with different types of benzyl bromide to prepare different substituted pentanitrogen guanidine salt chiral phase transfer catalysts PN. The synthesis method has simple reaction steps, milder reaction conditions and can obtain the target product more efficiently.
Description
Technical Field
The invention relates to the technical field of synthesis of pentanitrogen guanidine salt chiral phase transfer catalysts, in particular to a novel synthesis method of a pentanitrogen guanidine salt chiral phase transfer catalyst.
Background
The phase transfer catalyst catalysis is a novel organic synthesis method. The reaction which is difficult or impossible to occur by the conventional method can be smoothly performed by adopting the novel method. Therefore, research and application of the phase transfer catalyst are important points of research. Pentanitrogen guanidine salt (PN), an sp reported by the Chen Junfeng professor team in 2011 2 An asymmetric phase transfer catalyst (j.am. Chem. Soc.,2011,133,2828) with a hybridized nitrogen center, guanidine as a backbone. The existing synthesis method of the pentanitrogen guanidine salt chiral phase transfer catalyst, as disclosed in patent WO2012057709A1, mainly comprises the steps of reacting chiral ethylenediamine with triphosgene under the action of triethylamine to synthesize imidazoline; then the generated imidazoline reacts with methyl iodide in a nitrogen alkylation reaction under the action of sodium hydride, and then reacts with oxalyl chloride to obtain the imidazolium salt. The imidazolium salt is reacted with ammonia to synthesize the triazaguanidine, which is then combined with the imidazolium salt to form the pentazaguanidine salt chiral phase transfer catalyst.
The method has the problems of complicated steps, unsmooth operation and insufficient mild reaction conditions. In addition, the method is inconvenient to carry out the nitrogen alkylation reaction in the middle step and carry out other modification on the later catalyst. And the imidazolium salt is not easy to store, is sensitive to air and water, and affects the reaction efficiency. Therefore, the invention researches a novel synthesis method of the pentanitrogen guanidine salt chiral phase transfer catalyst.
Disclosure of Invention
The invention provides a novel synthesis method of a pentanitrogen guanidine salt chiral phase transfer catalyst, aiming at the problems existing in the current synthesis method of the pentanitrogen guanidine salt chiral phase transfer catalyst.
The invention provides a novel synthesis method of a pentanitrogen guanidine salt chiral phase transfer catalyst, which comprises the following steps:
s1, reacting chiral 1, 2-diphenyl-1, 2-ethylenediamine and cyanogen bromide serving as reactants in acetonitrile solvent at the reaction temperature of 70-90 ℃ for 10-14h to obtain chiral 2-iminoimidazolinium salt.
The specific method comprises the following steps: firstly, chiral 1, 2-diphenyl-1, 2-ethylenediamine is added into a reaction vessel, acetonitrile solution of cyanogen bromide is added into the reaction vessel under the nitrogen atmosphere and at the temperature of 0 ℃, the temperature is increased to 80-90 ℃ for reaction for 10-14 hours, after the reaction is finished, the solvent is decompressed and concentrated, and the chiral 2-iminoimidazolinium salt is obtained through silica gel column chromatography separation and purification.
S2, taking chiral 1, 2-diphenyl-1, 2-ethylenediamine and 3, 5-di-tert-butyl bromobenzyl as reactants, and stirring and reacting for 10-14h in acetonitrile solvent at room temperature to obtain chiral secondary amine.
The specific method of the step is as follows: firstly, adding chiral 1, 2-diphenyl-1, 2-ethylenediamine and potassium carbonate into a reaction vessel, and adding acetonitrile for dissolution; slowly dripping an acetonitrile solution of 3, 5-di-tert-butyl bromobenzyl into a reaction vessel, stirring at room temperature for reaction for 10-14h, and separating and purifying after the reaction is finished to obtain chiral secondary amine.
S3, stirring and reacting the chiral secondary amine prepared in the step S2 with thiophosgene in a mixed solvent of dichloromethane and water at room temperature for 0.5-2h to obtain chiral thiourea.
The specific method of the step is as follows: adding the chiral secondary amine and potassium carbonate obtained in the step S2 into a reaction container, adding dichloromethane and water to dissolve the chiral secondary amine and potassium carbonate, dripping a dichloromethane solution of thiophosgene into the reaction container at the temperature of 0 ℃, stirring at room temperature for reaction for 0.5-2h, and separating and purifying after the reaction is finished to obtain chiral thiourea.
S4, dissolving the chiral thiourea prepared in the step S3 in toluene, adding oxalyl chloride, and reacting at 70-90 ℃ for 8-12 hours to prepare an intermediate; and (2) reacting the intermediate with the chiral 2-iminoimidazolium salt prepared in the step (S1) in acetonitrile solvent at the temperature of 70-90 ℃ for 1-3h to prepare the pentanitrogen guanidine salt intermediate NH-PN.
The method specifically comprises the following steps: adding the chiral thiourea obtained in the step S3 into a reaction container, adding toluene to dissolve the chiral thiourea in a nitrogen atmosphere, then adding oxalyl chloride, reacting for 8-12h at 70-90 ℃, and concentrating the toluene under reduced pressure after the reaction is finished; and then adding the chiral 2-imine imidazolinium salt prepared in the step S1 into a reaction container, adding acetonitrile under the nitrogen atmosphere for dissolution, adding triethylamine, reacting for 1-3 hours at 70-90 ℃, then cooling to room temperature, stirring overnight, separating and purifying to obtain a pentanitrogen guanidine salt intermediate NH-PN.
S5, adding the pentanitrogen guanidine salt intermediate NH-PN, potassium carbonate and benzyl bromide compound obtained in the step S4 into a reaction vessel, adding methylene dichloride for dissolution, stirring at room temperature for reaction for 22-26 hours, and separating and purifying after the reaction is finished to obtain the pentanitrogen guanidine salt chiral phase transfer catalyst PN. The benzyl bromide compound is selected from one of 4-fluoro-2-nitrobenzyl bromide, 2-nitro-4-cyanobenzyl bromide, 2-cyano-5-fluorobenzyl bromide, 2-cyanobenzyl bromide and 3, 5-bis (trifluoromethyl) benzyl bromide. According to different types of selected benzyl bromide compounds, different chiral phase transfer catalysts PN of pentanitrogen guanidine salts can be further prepared.
Preferably, in step S1, the reaction conditions are: the reaction was carried out at a temperature of 80℃for 12h.
Preferably, in step S2, the reaction conditions are: the reaction was stirred at room temperature for 12h.
Preferably, in step S3, the reaction conditions are: the reaction was stirred at room temperature for 1h.
Preferably, in the step S4, the reaction condition for preparing the intermediate by reacting the chiral thiourea with oxalyl chloride is 80 ℃ for 10 hours. The intermediate is reacted with the chiral 2-iminoimidazolium salt at 80 ℃ for 2 hours.
Preferably, in step S5, the reaction conditions are: the reaction was stirred at room temperature for 24h.
Compared with the prior art, the invention has the following advantages:
(1) Compared with the existing synthesis method of the pentanitrogen guanidine salt chiral phase transfer catalyst, the synthesis method has the advantages of simple reaction steps, milder reaction conditions and higher efficiency in obtaining the target product.
(2) The method of the invention avoids the problem of loss in the storage process and experimental operation by the method of generating the imidazolium salt in the reaction, and greatly improves the experimental efficiency.
(3) According to the method, the pentanitrogen guanidine salt chiral phase transfer catalyst skeleton is synthesized, and then the corresponding chiral catalyst is synthesized through the nitrogen alkylation reaction, so that the catalyst is more convenient to modify in the later period, and the time and cost for modifying the catalyst in the later period are greatly reduced.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance analysis of pentanitrogen guanidine salt intermediate NH-PN prepared in example 1.
FIG. 2 is a chart of nuclear magnetic resonance carbon analysis of pentanitrogen guanidine salt intermediate NH-PN prepared in example 1.
FIG. 3 is a chart showing the hydrogen nuclear magnetic resonance analysis of the chiral phase transfer catalyst PN1 prepared in example 2.
FIG. 4 is a chart showing the analysis of nuclear magnetic resonance carbon spectrum of the chiral phase transfer catalyst PN1 prepared in example 2.
FIG. 5 is a chart showing nuclear magnetic resonance fluorine spectrum analysis of the chiral phase transfer catalyst PN1 prepared in example 2.
FIG. 6 is a chart showing the hydrogen nuclear magnetic resonance analysis of the chiral phase transfer catalyst PN2 prepared in example 3.
FIG. 7 is a chart showing the nuclear magnetic resonance carbon spectrum of the chiral phase transfer catalyst PN2 prepared in example 3.
FIG. 8 is a chart showing the hydrogen nuclear magnetic resonance analysis of the chiral phase transfer catalyst PN3 prepared in example 4.
FIG. 9 is a chart showing the nuclear magnetic resonance carbon spectrum of the chiral phase transfer catalyst PN3 prepared in example 4.
FIG. 10 is a chart showing nuclear magnetic resonance fluorine spectrum analysis of the chiral phase transfer catalyst PN3 prepared in example 4.
FIG. 11 is a chart showing the hydrogen nuclear magnetic resonance analysis of the chiral phase transfer catalyst PN4 prepared in example 5.
FIG. 12 is a chart showing the nuclear magnetic resonance carbon spectrum of the chiral phase transfer catalyst PN4 prepared in example 5.
FIG. 13 is a chart showing the hydrogen nuclear magnetic resonance analysis of the chiral phase transfer catalyst PN5 prepared in example 6.
FIG. 14 is a chart showing the nuclear magnetic resonance carbon spectrum of the chiral phase transfer catalyst PN5 prepared in example 6.
FIG. 15 is a chart showing nuclear magnetic resonance fluorine spectrum analysis of the chiral phase transfer catalyst PN5 prepared in example 6.
Detailed Description
The preferred embodiments of the present invention will be described below with reference to the accompanying drawings, it being understood that the preferred embodiments described herein are for illustration and explanation of the present invention only, and are not intended to limit the present invention.
Example 1
The invention provides a new synthesis method of a pentanitrogen guanidine salt chiral phase transfer catalyst, which comprises the steps of firstly preparing a pentanitrogen guanidine salt intermediate NH-PN; the preparation method comprises the following specific steps:
s1: chiral 1, 2-diphenyl-1, 2-ethylenediamine A (2.55 g,12mmol,1.0 equiv) was added into a round bottom flask, cyanogen bromide (1.53 g,14.4mmol,1.2 equiv) was dissolved in dry acetonitrile, and then added into a reaction flask at 0 ℃ under nitrogen atmosphere, followed by heating to 80 ℃ for reaction for 12 hours, after the reaction was completed, the solvent was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (ethyl acetate) to obtain pale yellow chiral 2-iminoimidazolium salt B.
S2: chiral 1, 2-diphenyl-1, 2-ethylenediamine a (2.12 g,10mmol,1.0 equiv) and potassium carbonate (5.53 g,40mmol,4.0 equiv) were added to a round bottom flask, acetonitrile (40 ml) was added to dissolve, 3, 5-di-tert-butylbromobenzyl C (5.64 g,20mmol,2.0 equiv) was dissolved in acetonitrile (30 ml), slowly added dropwise to a reaction flask over 1h by a syringe pump, followed by stirring at room temperature for 12h, quenching by adding water (20 ml) after completion of the reaction, followed by extraction with dichloromethane (30 ml×3), the obtained organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to give a pale yellow chiral secondary amine D.
S3: synthetic chiral secondary amine D (3.56 g,5.8mmol,1.0 equiv) and potassium carbonate (2.4 g,17.4mmol,3.0 equiv) were placed in a round bottom flask, dissolved by adding dichloromethane (20 ml) and water (20 ml), a solution of thiophosgene (575 μl,7.54mmol,1.3 equiv) in dichloromethane (5 ml) was added dropwise to the reaction flask at 0 ℃, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml×3) after the reaction was completed, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=40:1) to give pale yellow chiral thiourea E.
S4: the chiral thiourea E (2.5 g,3.8mmol,1.0 equiv) obtained was placed in a 100ml round bottom flask, dissolved by adding dry toluene (10 ml) under nitrogen atmosphere, and then oxalyl chloride (3.2 ml,38mmol,10.0 equiv) was added, followed by reaction at 80℃for 10 hours. After completion of the reaction, toluene was quickly dried, chiral 2-iminoimidazolium salt B (1.1 g,3.42mmol,0.9 equiv) was then added to the reaction flask, dried acetonitrile (16 ml) was added under nitrogen atmosphere to dissolve, triethylamine (2.13 ml,15.2mmol,4.0 equiv) was further added, and the mixture was reacted at 80℃for two hours, and then cooled to room temperature and stirred overnight. After the reaction is finished, the solvent can be directly concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to obtain a pale yellow pentanitrogen guanidine salt intermediate NH-PN with the yield of 56%.
The chemical reaction principle of the four steps is as follows:
nuclear magnetic analysis was performed on the pentanitrogen guanidine salt intermediate NH-PN prepared in example 1, and fig. 1 is a diagram of nuclear magnetic resonance hydrogen spectrum analysis. FIG. 2 is a chart of nuclear magnetic resonance spectroscopy. In fig. 1, 1H NMR (400 mhz, chloroform-d) delta 7.61 (s, 2H), 7.37-7.33 (m, 6H), 7.32-7.28 (m, 4H), 7.26-7.20 (m, 6H), 7.18-7.10 (m, 6H), 6.94 (d, j=1.8 hz, 4H), 4.92 (s, 2H), 4.80 (s, 2H), 4.72-4.62 (m, 4H), 1.25 (s, 36H). In the view of figure 2, 13 c NMR (101 MHz, chlorine-d). Delta. 163.5,158.8,150.8,138.7,135.4,134.3,129.1,129.0,128.6,128.5,126.8,123.0,121.5,71.3,67.6,51.0,34.7,31.4. The nuclear magnetic analysis proves that the pentanitrogen guanidine salt intermediate NH-PN is successfully prepared by the preparation method.
The pentanitrogen guanidine salt intermediate NH-PN prepared in example 1 is further reacted with benzyl bromide compound in solvent dichloromethane to prepare a series of chiral phase transfer catalysts PN of pentanitrogen guanidine salt with similar structure. Specific examples are as follows:
example 2
Pentanitrogen guanidine salt intermediate NH-PN (200 mg,0.22mmol,1.0 equiv), potassium carbonate (121 mg,0.88mmol,4.0 equiv) and 4-fluoro-2-nitrobenzyl bromide (205.9 mg,0.88mmol,4.0 equiv) prepared in example 1 were placed in a round bottom flask, dichloromethane (3 ml) was added to dissolve, stirring was carried out at room temperature for 24 hours, the solvent was concentrated under reduced pressure directly after the reaction was completed, and then isolation and purification by silica gel column chromatography (petroleum ether: ethyl acetate=1:2) gave pale yellow pentanitrogen guanidine salt chiral phase transfer catalyst PN1 in 89% yield. The chemical reaction principle formula is as follows:
the chiral phase transfer catalyst PN1 prepared in example 2 was subjected to nuclear magnetic resonance analysis, and FIG. 3 is a diagram showing nuclear magnetic resonance hydrogen spectrum analysis. FIG. 4 is a chart of nuclear magnetic resonance spectroscopy. FIG. 5 is a chart of nuclear magnetic resonance fluorine analysis. In the view of figure 3 of the drawings, 1 h NMR (400 mhz, chloro form-d) delta 8.92-8.79 (m, 2H), 7.49-7.36 (m, 4H), 7.26-7.18 (m, 3H), 7.17-7.10 (m, 4H), 7.07-6.92 (m, 15H), 6.92-6.83 (m, 4H), 5.30 (d, j=14.2 hz, 2H), 5.21 (d, j=15.1 hz, 2H), 5.00 (d, j=14.1 hz, 2H), 4.84 (s, 2H), 4.47-4.35 (m, 4H), 1.16 (s, 36H). In the view of figure 4 of the drawings, 13 c NMR (101 mhz, chloro-d) δ 162.9,160.3,158.2 (d, j=192.6 Hz), 151.4,147.8 (d, j=8.3 Hz), 136.8 (d, j=7.7 Hz), 136.6,134.5,133.0,129.3,129.0,128.8,128.5,128.2,127.4,125.9,123.0,122.4,121.8 (d, j=20.6 Hz), 111.9 (d, j=26.9 Hz), 71.9,68.9,49.5,46.8,34.7,31.3. In the view of figure 5 of the drawings, 19 f NMR (376MHz, chloro form-d) delta-109.7. The nuclear magnetic analysis proves that the preparation method successfully prepares the product PN1.
Example 3
Pentazaguanidine salt intermediate NH-PN (200 mg,0.22mmol,1.0 equiv), potassium carbonate (121 mg,0.88mmol,4.0 equiv) and 2-nitro-4-cyanobenzyl bromide (212.1 mg,0.88mmol,4.0 equiv) prepared in example 1 were placed in a round bottom flask, dichloromethane (3 ml) was added to dissolve, stirring was carried out at room temperature for 24 hours, the solvent was concentrated under reduced pressure after the reaction was completed, and then isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:2) to give pale yellow pentazaguanidine salt chiral phase transfer catalyst PN2 in 84% yield. The chemical reaction principle formula is as follows:
nuclear magnetic analysis was performed on the chiral phase transfer catalyst PN2 prepared in example 3, and fig. 6 is a diagram of nuclear magnetic resonance hydrogen spectrum analysis. FIG. 7 is a chart of nuclear magnetic resonance spectroscopy. In the view of figure 6 of the drawings, 1 h NMR (400 mhz, chloroform-d) delta 9.39 (d, j=8.1 hz, 2H), 8.08-7.99 (m, 2H), 7.99-7.93 (m, 2H), 7.36-7.31 (m, 2H), 7.31-7.26 (m, 2H), 7.20-7.15 (m, 4H), 7.12-7.06 (m, 6H), 7.04-6.98 (m, 8H), 6.96-6.89 (m, 4H), 5.43 (d, j=14.2 hz, 2H), 5.29 (d, j=15.1 hz, 2H), 5.11 (d, j=13.9 hz, 2H), 5.01 (s, 2H), 4.49 (s, 2H), 4.42 (d, j=15.0 hz, 2H), 1.22 (s, 36H). In the view of figure 7 of the drawings, 13 c NMR (101 MHz, chlorine-d). Delta. 159.1,157.2,151.6,147.2,137.3,136.5,135.0,133.9,132.8,129.5,129.2,129.1,128.7,128.5,127.8,127.4,123.0,122.7,116.3,113.3,72.2,68.8,49.5,47.2,34.8,31.3,29.7. The nuclear magnetic analysis proves that the PN2 product is successfully prepared by the preparation method.
Example 4
Pentazaguanidine salt intermediate NH-PN (200 mg,0.22mmol,1.0 equiv), potassium carbonate (121 mg,0.88mmol,4.0 equiv) and 2-cyano-5-fluorobenzyl (188 mg,0.88mmol,4.0 equiv) prepared in example 1 were placed in a round bottom flask, dichloromethane (3 ml) was added for dissolution, stirring was carried out at room temperature for 24h, the solvent was concentrated under reduced pressure directly after the reaction was completed, and then isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:2) to give pale yellow pentazaguanidine salt chiral phase transfer catalyst PN3 in 84% yield. The chemical reaction principle formula is as follows:
nuclear magnetic analysis was performed on the chiral phase transfer catalyst PN3 prepared in example 4, and FIG. 8 is a nuclear magnetic resonanceResonance hydrogen spectrum analysis chart. FIG. 9 is a chart of nuclear magnetic resonance spectroscopy. FIG. 10 is a chart of nuclear magnetic resonance fluorine analysis. In the view of figure 8 of the drawings, 1 h NMR (400 mhz, chloroform-d) delta 7.72-7.63 (m, 2H), 7.45-7.40 (m, 2H), 7.32-7.27 (m, 4H), 7.25-7.20 (m, 4H), 7.19-7.08 (m, 10H), 7.06-6.96 (m, 11H), 5.20 (d, j=15.0 hz, 2H), 5.07 (d, j=14.6 hz, 2H), 4.80 (s, 2H), 4.73 (d, j=14.6 hz, 2H), 4.65 (s, 2H), 4.45 (d, j=15.0 hz, 2H), 1.20 (s, 36H). In the view of figure 9 of the drawings, 13 c NMR (101 mhz, chloro-d) δ 166.3,163.7,157.8 (d, j=114.1 Hz), 151.6,141.2 (d, j=9.1 Hz), 136.7,135.1 (d, j=9.1 Hz), 134.4,133.0,129.5 (4), 129.5 (0), 129.3,129.2,128.3,127.7,123.0,122.6,119.4 (d, j=24.2 Hz), 116.8,116.6,108.5 (d, j=3.0 Hz), 70.9,69.4,49.8,47.7,34.9,31.5. In the view of figure 10 of the drawings, 19 f NMR (376MHz, chloro form-d) delta-100.1. The nuclear magnetic analysis proves that the preparation method successfully prepares the product PN3.
Example 5
Pentazoguanidine salt intermediate NH-PN (200 mg,0.22mmol,1.0 equiv), potassium carbonate (121 mg,0.88mmol,4.0 equiv) and 2-cyanobenzyl bromide (173 mg,0.88mmol,4.0 equiv) prepared in example 1 were placed in a round bottom flask, dichloromethane (3 ml) was added to dissolve, stirred at room temperature for 24h, after the reaction was completed, the solvent was concentrated directly under reduced pressure, and then isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:2) to give pentazoguanidine salt chiral phase transfer catalyst PN4 as pale yellow in 99% yield. The chemical reaction principle formula is as follows:
nuclear magnetic analysis was performed on the chiral phase transfer catalyst PN4 prepared in example 5, and fig. 11 is a diagram of nuclear magnetic resonance hydrogen spectrum analysis. FIG. 12 is a chart of nuclear magnetic resonance spectroscopy. In the view of figure 11 of the drawings, 1 h NMR (400 mhz, chloroform-d) delta 7.87 (d, j=7.8 hz, 2H), 7.65-7.56 (m, 2H), 7.48-7.43 (m, 2H), 7.37-7.29 (m, 6H), 7.25-7.11 (m, 10H), 7.08-7.03 (m, 4H), 7.01-6.97 (m, 4H), 6.96-6.93 (m, 4H), 5.19 (d, j=14.8 hz, 2H), 5.03 (d, j=14.7 hz, 2H), 4.74-4.65 (m, 4H), 4.51 (s, 2H), 4.34 (d, j=14.8 hz, 2H), 1.19 (s, 36H). In the view of figure 12 of the drawings, 13 CNMR(101Mhz, color-d) delta 158.0,156.6,151.5,137.2,136.8,134.5,133.8,132.7,132.5,131.6,129.4,129.3,129.3,129.1,129.0,127.9,127.3,123.0,122.5,117.3,112.1,70.6,68.8,49.4,47.5,34.7,31.3. The nuclear magnetic analysis proves that the preparation method successfully prepares the product PN4.
Example 6
Pentazaguanidine salt intermediate NH-PN (200 mg,0.22mmol,1.0 equiv), potassium carbonate (121 mg,0.88mmol,4.0 equiv) and 3, 5-bistrifluoromethyl-bromobenzyl (270 mg,0.88mmol,4.0 equiv) prepared in example 1 were placed in a round-bottomed flask, dichloromethane (3 ml) was added for dissolution, stirring was carried out at room temperature for 24 hours, and after completion of the reaction the solvent was concentrated under reduced pressure, and then isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:2) to give pale yellow pentazaguanidine salt chiral phase transfer catalyst PN5 in 46% yield. The chemical reaction principle formula is as follows:
nuclear magnetic resonance analysis was performed on the chiral phase transfer catalyst PN5 prepared in example 6, and FIG. 13 is a chart of nuclear magnetic resonance hydrogen analysis. FIG. 14 is a chart of nuclear magnetic resonance spectroscopy. FIG. 15 is a chart of nuclear magnetic resonance fluorine analysis. In the view of figure 13 of the drawings, 1 h NMR (400 mhz, chloroform-d) delta 7.68-7.63 (m, 2H), 7.59-7.54 (m, 4H), 7.29 (t, j=1.8 hz, 2H), 7.25-7.08 (m, 16H), 6.91-6.82 (m, 8H), 5.28-5.14 (m, 4H), 5.04 (s, 2H), 4.84 (d, j=15.9 hz, 2H), 4.56 (s, 2H), 4.24 (d, j=14.7 hz, 2H), 1.18 (s, 36H). In the view of figure 14 of the drawings, 13 c NMR (101 mhz, chloro form-d) δ 158.0,157.5,151.6,137.7,136.4,134.9,132.5,132.0 (q, j=33.3 Hz), 129.8,129.5,129.3,129.2,128.6,128.5,127.5,123.1,122.9 (q, j= 274.7 Hz), 122.8,122.0,70.7,68.5,50.2,49.8,34.8,31.4. In the view of figure 15 of the drawings, 19 f NMR (376 MHz, chloro form-d) delta-62.9. The nuclear magnetic analysis proves that the preparation method successfully prepares the product PN5.
The present invention is not limited to the above-mentioned embodiments, but is intended to be limited to the following embodiments, and any modifications, equivalents and modifications can be made to the above-mentioned embodiments without departing from the scope of the invention.
Claims (8)
1. A synthesis method of a pentanitrogen guanidine salt chiral phase transfer catalyst is characterized by comprising the following steps:
s1, chiral 1, 2-diphenyl-1, 2-ethylenediamine and cyanogen bromide are used as reactants, and the chiral 2-imine imidazolinium salt is obtained by reacting for 10 to 14 hours at the reaction temperature of 70 to 90 ℃ in acetonitrile solvent;
s2, taking chiral 1, 2-diphenyl-1, 2-ethylenediamine and 3, 5-di-tert-butyl bromobenzyl as reactants, and stirring and reacting for 10-14h in acetonitrile solvent at room temperature to obtain chiral secondary amine;
s3, stirring and reacting the chiral secondary amine prepared in the step S2 with thiophosgene in a mixed solvent of dichloromethane and water at room temperature for 0.5-2h to obtain chiral thiourea;
s4, dissolving the chiral thiourea prepared in the step S3 in toluene, adding oxalyl chloride, and reacting at 70-90 ℃ for 8-12 hours to prepare an intermediate; reacting the intermediate with the chiral 2-iminoimidazolium salt prepared in the step S1 in acetonitrile solvent at the temperature of 70-90 ℃ for 1-3h to prepare pentanitrogen guanidine salt intermediate NH-PN;
s5, reacting the pentanitrogen guanidine salt intermediate NH-PN prepared in the step S4 with benzyl bromide compounds in methylene dichloride serving as a solvent at room temperature for 22-26 hours to prepare the pentanitrogen guanidine salt chiral phase transfer catalyst PN.
2. The method for synthesizing a pentanitrogen guanidine salt chiral phase transfer catalyst according to claim 1, wherein the benzyl bromide compound is one selected from the group consisting of 4-fluoro-2-nitrobenzyl bromide, 2-nitro-4-cyanobenzyl bromide, 2-cyano-5-fluorobenzyl bromide, 2-cyanobenzyl bromide and 3, 5-bistrifluoromethylbenzyl bromide.
3. The method for synthesizing the pentanitrogen guanidine salt chiral phase transfer catalyst according to claim 1, wherein the step S1 specifically comprises: firstly, chiral 1, 2-diphenyl-1, 2-ethylenediamine is added into a reaction vessel, acetonitrile solution of cyanogen bromide is added into the reaction vessel under the nitrogen atmosphere and at the temperature of 0 ℃, the temperature is increased to 80-90 ℃ for reaction for 10-14 hours, after the reaction is finished, the solvent is decompressed and concentrated, and the chiral 2-iminoimidazolinium salt is obtained through silica gel column chromatography separation and purification.
4. The method for synthesizing the pentanitrogen guanidine salt chiral phase transfer catalyst according to claim 1, wherein the step S2 specifically comprises: firstly, adding chiral 1, 2-diphenyl-1, 2-ethylenediamine and potassium carbonate into a reaction vessel, and adding acetonitrile for dissolution; slowly dripping an acetonitrile solution of 3, 5-di-tert-butyl bromobenzyl into a reaction vessel, stirring at room temperature for reaction for 10-14h, and separating and purifying after the reaction is finished to obtain chiral secondary amine.
5. The method for synthesizing the pentanitrogen guanidine salt chiral phase transfer catalyst according to claim 1, wherein the step S3 specifically comprises: adding the chiral secondary amine and potassium carbonate obtained in the step S2 into a reaction container, adding dichloromethane and water to dissolve the chiral secondary amine and potassium carbonate, dripping a dichloromethane solution of thiophosgene into the reaction container at the temperature of 0 ℃, stirring at room temperature for reaction for 0.5-2h, and separating and purifying after the reaction is finished to obtain chiral thiourea.
6. The method for synthesizing the pentanitrogen guanidine salt chiral phase transfer catalyst according to claim 1, wherein the step S4 specifically comprises: adding the chiral thiourea obtained in the step S3 into a reaction container, adding toluene to dissolve the chiral thiourea in a nitrogen atmosphere, then adding oxalyl chloride, reacting for 8-12h at 70-90 ℃, and concentrating the toluene under reduced pressure after the reaction is finished; and then adding the chiral 2-imine imidazolinium salt prepared in the step S1 into a reaction container, adding acetonitrile under the nitrogen atmosphere for dissolution, adding triethylamine, reacting for 1-3h at 70-90 ℃, then cooling to room temperature, stirring overnight, separating and purifying to obtain the pentanitrogen guanidine salt chiral phase transfer catalyst NH-PN.
7. The method for synthesizing the pentanitrogen guanidine salt chiral phase transfer catalyst according to claim 2, wherein the step S5 specifically comprises: adding the pentanitrogen guanidine salt intermediate NH-PN, potassium carbonate and benzyl bromide compound obtained in the step S4 into a reaction vessel, adding methylene dichloride for dissolution, stirring at room temperature for reaction for 22-26h, and separating and purifying after the reaction is finished to obtain the pentanitrogen guanidine salt chiral phase transfer catalyst PN.
8. A pentanitrogen guanidine salt chiral phase transfer catalyst characterized by being prepared by the synthetic method of the pentanitrogen guanidine salt chiral phase transfer catalyst according to any one of claims 1-7.
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