CN114105993A - Synthesis method of chiral pyrroloimidazole compound - Google Patents
Synthesis method of chiral pyrroloimidazole compound Download PDFInfo
- Publication number
- CN114105993A CN114105993A CN202110720046.0A CN202110720046A CN114105993A CN 114105993 A CN114105993 A CN 114105993A CN 202110720046 A CN202110720046 A CN 202110720046A CN 114105993 A CN114105993 A CN 114105993A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- chiral
- compound
- ammonium
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing chiral pyrroloimidazole compounds by asymmetric catalytic reaction. Alpha-aminoketone and alpha, beta-unsaturated aldehyde are subjected to cyclization reaction under the action of a chiral secondary amino catalyst and an additive, and the chiral pyrroloimidazole compound is obtained through reduction dehydration and further cyclization. The method is simple to operate, low in cost and high in yield, and provides a new idea for efficient synthesis of the compounds.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis methods, and particularly relates to a synthesis method for preparing chiral pyrroloimidazole compounds through asymmetric catalytic reaction.
Background
The pyrroloimidazole compounds have wide application in the aspects of medicines, complexes, polymers and the like, and the preparation of the compounds mainly comprises the following methods (Scheme 1):
one is as follows: the substituted nitrile and the substituted 5-azido-1-alkyne are prepared by a [2+3] cycloaddition reaction. (Scheme 1, equation 1)
The second step is as follows: the side product of the pyrroloimidazole is separated from the reaction of three components of imidazole aldehyde, amine and alkyne promoted by silver. (Scheme 1, equation 2)
And thirdly: a series of pyrroloimidazoles were synthesized using a domino reaction. (Scheme 1, equation 3)
Fourthly, the method comprises the following steps: at Na/NH3、Bu3The 5-bromo-1- (butene-3-yl) -2-methylimidazole is reduced and cyclized in an SnH system to obtain a dicyclic product. (Scheme 1, equation 4)
And fifthly: prepared by multi-step reaction of multifunctional molecules. (Scheme 1, equation 5)
And the sixth step: chiral raw materials are subjected to various kinds of reactions to prepare the chiral pyrroloimidazole. (Scheme 1, equation 6)
Disclosure of Invention
The invention aims to provide a novel synthetic method for preparing a compound with a chiral pyrroloimidazole structure shown in a general formula I by three-step reaction of alpha-aminoketone (compound A) and alpha, beta-unsaturated aldehyde (compound B) under the action of a chiral secondary amine catalyst and an additive, wherein the reaction is asymmetric cyclization, selective hydroxyl reduction and racemization-free ring closure. The method is simple to operate, low in cost and high in yield, and provides a new idea for efficient synthesis of the compounds.
The above purpose of the invention is realized by the following technical scheme:
a method for synthesizing chiral pyrroloimidazole compounds; under the action of a chiral secondary amine catalyst and an additive, alpha-aminoketone (compound A) and alpha, beta-unsaturated aldehyde (compound B) are subjected to three-step reaction of asymmetric cyclization, selective hydroxyl reduction and racemization-free ring closure to prepare a compound with a chiral pyrroloimidazole structure shown in a general formula I;
the first step is as follows: asymmetric cyclization; in a proper solvent, alpha-aminoketone (compound A) and alpha, beta-unsaturated aldehyde (compound B) are subjected to one-step cyclization reaction under the action of a chiral secondary amino catalyst and an additive to obtain a compound C;
the second step is that: selective hydroxyl reduction; dehydrating and reducing the compound C to obtain a diastereoisomer mixture, namely a compound D;
the third step: no racemization closed ring; further cyclizing and aromatizing the compound D to obtain a compound with a chiral pyrroloimidazole structure shown in a general formula 1;
wherein: r1Is C6-C20Any one of alkylphenyl, alkoxyphenyl, carboxylate phenyl, halophenyl, nitrophenyl, cyanophenyl, biphenyl, naphthyloxyphenyl, trifluoromethylphenyl, trichloromethylphenyl, and trifluoromethoxyphenyl, or di-or tri-substituted phenyl with the above functional group at different positions; ferrocenyl; 2-thienyl, 3-thienyl; 2-furyl group, 3-furyl group; pyridyl substituted at the 2-, 3-or 4-position; n-methyl-3, 4 or 5-indolyl; including perfluorocarboxyalkyl (Rf) groups containing 1-10 carbons.
R2Is C1-C6Alkyl of (C)6-C20The phenyl group is one of alkyl phenyl, alkoxy phenyl, halogenated phenyl, nitro phenyl, nitrile phenyl, biphenyl, naphthoxy phenyl, trifluoromethyl phenyl, trichloromethyl phenyl and trifluoromethoxyphenyl, or a disubstituted or trisubstituted phenyl group with functional groups on the benzene ring at different positions.
R3Is C6-C20Alkyl phenyl, alkoxy phenyl, carboxylate phenyl, halogen phenyl, nitro phenyl, nitrile phenyl, biphenyl, naphthoxy phenyl,One of trifluoromethyl phenyl, trichloromethyl phenyl and trifluoro methoxy phenyl, or the disubstituted or trisubstituted phenyl of the functional group at different positions; ferrocenyl; 2-thienyl, 3-thienyl; 2-furyl group, 3-furyl group; pyridyl substituted at the 2-, 3-or 4-position; n-methyl-3, 4 or 5-indolyl.
In the first step, the chiral secondary amino catalyst is alpha, alpha diphenyl prolinol trimethylsilyl ether or alpha, alpha-bis- (3,5) -bistrifluoromethylphenyl prolinol trimethylsilyl ether, and accounts for 0.1-50% mol of the mass of alpha, beta-unsaturated aldehyde.
In the first step, the additive is not added or is C2-C6Alkyl carboxylic acid of (2), C2-C6Alkyl sulfonic acid, C6-C20Aryl sulfonic acid, binaphthol phosphonic acid, C7-C10 substituted benzoic acid and polyacrylic acid, potassium acetate, triethylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), 7-methyl-1, 5, 7-triazabicyclo [4.4.0]Dec-5-ene (MTBD), 1, 4-diazabicyclo [2.2.2]Octane (DABCO), Triazabicyclo (TBD), Tetramethylguanidine (TMG).
In the first step, the solvent is at least one of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, ethyl acetate, benzene, toluene, acetone, acetonitrile, diethyl ether, methanol, ethanol, DMF, DMSO, and NMP.
In the first step, the additive is preferably benzoic acid.
In the second step, the dehydroxylation reduction of the compound C to prepare the compound D takes dichloromethane as a reducing agent and triethylsilane as a reducing agent and is carried out in the presence of trifluoroacetic acid or boron trifluoride diethyl etherate.
And in the third step, the reaction solvent in the cyclization aromatization is at least one of acetonitrile, acetone, trifluoroacetic acid, acetic acid, diethylene glycol dimethyl ether, DMF, DMAC, HMP, DMI, DMSO and NMP.
In the third step, the ammonia source is at least one of ammonium sulfate, ammonium bisulfate, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium fluoride, ammonium bromide, ammonium iodide, ammonium acetate, methanol solution of ammonia and ammonia water with 1-50 equivalent.
In the third step of cyclization aromatization, the additive can be not added, or 0-10 mol% of one of acetic acid, formic acid, trifluoroacetic acid, propionic acid and benzoic acid.
The invention adopts the following specific synthesis method: 0.1 to 50mol percent of secondary amine catalyst and 0.1 to 50mol percent of additive are mixed, methylene dichloride is dissolved, 1 equivalent of alpha, beta-unsaturated aldehyde (B) and 1.2 equivalents of alpha-aminoketone (A) are added after stirring for 30 min. After 24 hours of reaction at the temperature of minus 10-40 ℃, 4mL of dichloromethane is added, and triethylsilane, trifluoroacetic acid and glacial alcohol are added for bath overnight. TLC (P/E3/1) and the reaction was complete. And (4) performing column chromatography to obtain a product. Accurately weighing column chromatography, adding diethylene glycol dimethyl ether, 0-10 mol% acetic acid and 1-50 equivalent ammonium acetate, and reacting at 100 deg.C for 5 hr. TLC (P/E1/1) and the reaction was complete. And purifying the obtained mixture by column chromatography or crystallization to obtain the target product.
Unless otherwise indicated, the terms used herein have the following meanings.
The term "alkyl" as used herein includes straight chain and branched chain alkyl groups. Reference to a single alkyl group, such as "methyl", is intended to refer only to straight chain alkyl groups, and reference to a single branched alkyl group, such as "isopropyl", is intended to refer only to branched alkyl groups. For example, "C4The following alkyl groups "include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like. Similar rules apply to other groups used in this specification.
The term "halogen" as used herein includes fluorine, chlorine, bromine, iodine.
The amide substituents R of the aminoketone substrate in the above reaction scheme are listed in Table 11The concrete structure of (1). But is not limited to these structures.
TABLE 1R1Structure of substituent
The amide substituents R of the aminoketone substrate in the above reaction scheme are listed in Table 22The concrete structure of (1). But is not limited to these structures.
TABLE 2R2Structure of substituent
In the above reaction formula, R is shown in Table 33The specific structure of the substituent of each starting compound. But is not limited to these structures.
TABLE 3R3Structure of substituent
The structures of specific compounds 1 to 27 prepared by the present invention represented by the general formula I are shown below, but the present invention is not limited to these compounds.
The specific synthetic process of the compounds 1-27 is detailed in examples 1 and 20-36; structural warp1H NMR or LC-MS, and the chirality was confirmed by HPLC.
Compared with the content disclosed by the prior art, the invention has the advantages that:
the invention uses alpha, beta-unsaturated aldehyde and alpha-aminoketone to synthesize pyrrolidine compounds, and then cyclizes and synthesizes pyrroloimidazole compounds, thereby further improving the conversion efficiency. The method is simple to operate, low in cost and high in yield, and provides a new idea for efficient synthesis of the compounds.
Drawings
FIG. 1 is a diagram showing the analysis of a racemic body liquid phase of Compound 16 obtained in the present invention;
FIG. 2 is a liquid phase analysis diagram of chiral samples of compound 16 obtained by the present invention.
Detailed Description
The following non-limiting examples are presented to enable those of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way. The test methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified. In the following examples, the product chiral analysis involved instruments:
HPLC analytical equipment: agilent 1100
Chiral liquid phase column: daicel Chiralpak AD-H column
Mobile phase: hexane/i-PrOH.7/3
Example 1
Accurately weighing benzoic acid (8.3mg, 0.068mmol) and alpha, alpha-diphenylprolinol silyl ether catalyst (22mg, 0.068mmol) in a 10mL reaction flask, adding 1mL dichloromethane, stirring at room temperature for 30min, adding cinnamaldehyde (50mg, 0.3725mmol) and PhCONHCH2COCH3(60mg, 0.3386mmol) was stirred and reacted in an ice-water bath for 24h, followed by addition of 4mL of dichloromethane, addition of 1mL of triethylsilane, 1mL of trifluoroacetic acid and ice-alcohol bath overnight. TLC (P/E3/1) and the reaction was complete. The dr value of the diastereomer mixture (D) is determined by1H NMR measurement, cis (cis): trans (trans) ═ 1:1.3, ee ═ cis 97%/(trans) 98%. Column chromatography is carried out to obtain a cis-trans mixture of chiral substituted pyrrolidine intermediate, and the yield Y is 79%.
The cis-trans mixture (29.3mg, 0.1mmol) obtained by column chromatography was weighed out accurately, and 0.5mL of diethylene glycol dimethyl ether, ammonium acetate (116mg, 1.5mmol, 15eq.), 10. mu.L of acetic acid, and reacted at 100 ℃ for 5 hours. TLC (P/E1/1) and the reaction was complete. And (4) performing column chromatography to obtain a product. The yield is nuclear magnetic yield, the internal standard is dimethyl terephthalate, and Y is 95.6%. The product is obtained by column chromatography, Y is 78 percent, ee is 96 percent.
The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.81(dd,J＝5.2,3.3Hz,2H),7.43(dd,J＝10.5,4.8Hz,2H),7.38-7.21(m,8H),4.37(dd,J＝15.1,7.6Hz,1H),4.31(ddd,J＝10.7,8.2,4.6Hz,1H),4.19(dt,J＝10.7,7.4Hz,1H),3.09(dtd,J＝12.7,7.8,4.6Hz,1H),2.59(ddd,J＝15.3,12.9,7.2Hz,1H),1.98(d,J＝0.7Hz,3H).
example 2
This example differs from example 1 in that the additive in the first step is replaced by benzoic acid instead of no additive. The diastereomer mixture (D) dr ═ 1:3.3, ee ═ 95%/77%. The nuclear magnetic yield Y of the ring formation of the chiral pyrrolo-imidazole ring is 77 percent.
Example 3
This example differs from example 1 in that the additive in the first step is changed from benzoic acid to basic DBU. Diastereomer mixture (D) dr ═ 1:1.7, ee ═ 96%/97%, chiral pyrroloimidazole ring annulation nuclear magnetic yield Y ═ 22%.
Example 4
This example differs from example 1 in that the additive in the first step was changed from benzoic acid to 4-chlorobenzoic acid. The cis-trans mixture intermediate dr is 2:1, ee 96%/95%. The nuclear magnetic yield Y of the chiral pyrrole imidazole ring formation is 44 percent.
Example 5
This example differs from example 1 in that the additive in the first step is replaced by benzoic acid to 4-nitroformic acid. The product dr is 1:1 and ee is 96%/98%. The nuclear magnetic yield Y of the chiral pyrrole imidazole ring cyclization is 57 percent.
Example 6
This example differs from example 1 in that the additive in the first step is replaced by 4-methoxybenzoic acid instead of benzoic acid. The cis-trans mixture intermediate dr is 1.7:1, ee 96%/97%. The nuclear magnetic yield Y of chiral pyrrole imidazole ring formation is 76%.
Example 7
This example differs from example 1 in that the additive in the first step is replaced by 4-methylbenzoic acid instead of benzoic acid. The cis-trans mixture intermediate dr is 3:1, ee 96%/90%. The nuclear magnetic yield Y of the chiral pyrrole imidazole ring formation is 64.8%.
Example 8
This example differs from example 1 in that the solvent in the first step was changed from DCM to THF. The cis-trans mixture intermediate dr is 1.7:1, ee 96%/99%. The nuclear magnetic yield Y of the chiral pyrrole imidazole ring formation is 26 percent.
Example 9
This example differs from example 1 in that the first solvent was changed from DCM to AcOEt. The cis-trans mixture intermediate dr is 1:1.4, ee is 96%/96%. The nuclear magnetic yield Y of the chiral pyrrole imidazole ring cyclization is 39 percent.
Example 10
This example differs from example 1 in that the solvent in the first step was changed from DCM to MTBE. The cis-trans mixture intermediate dr is 1.4:1, ee 96%/97%. The nuclear magnetic yield Y of the chiral pyrrole imidazole ring cyclization is 25 percent.
Example 11
This example differs from example 1 in that the solvent in the first step was changed from DCM to PhMe. The cis-trans mixture intermediate dr is 1:2.25, ee 96%/89%. The nuclear magnetic yield Y of the ring formation of the chiral pyrrolo-imidazole ring is 52 percent.
Example 12
This example differs from example 1 in that the first solvent step is changed from DCM to CH3And (5) OH. The cis-trans mixture intermediate dr is 2.5:1, ee 96%/98%. The nuclear magnetic yield Y of the chiral pyrrole imidazole ring cyclization is 25 percent.
Example 13
This example differs from example 1 in that the first solvent step is changed from DCM to CH3And (5) OH. The cis-trans mixture intermediate dr is 1.1:1, ee 97%/99%. The nuclear magnetic yield Y of the chiral pyrrole imidazole ring cyclization is 19 percent.
Example 14
This example differs from example 1 in that in the third step 0.5mL of diethylene glycol dimethyl ether was changed to 2mL of acetic acid. The nuclear magnetic yield of chiral pyrrolo-imidazole ring formation is 28 percent, and ee is 83 percent.
Example 15
This example differs from example 1 in that in the third step 0.5mL of diethylene glycol dimethyl ether was changed to 1mL of acetic acid. The nuclear magnetic yield of chiral pyrrolo-imidazole ring formation is 33 percent, and ee is 94 percent.
Example 16
This example differs from example 1 in that the third step changed 0.5mL of diethylene glycol dimethyl ether to 0.5mL of acetic acid. The nuclear magnetic yield of chiral pyrrolo-imidazole ring formation is 62 percent, and ee is 94 percent.
Example 17
This example differs from example 1 in that the third step changed 0.5mL of diethylene glycol dimethyl ether to 0.3mL of acetic acid. The nuclear magnetic yield Y of the ring formation of the chiral pyrrolo-imidazole ring is 35 percent, and ee is 92 percent.
Example 18
This example differs from example 1 in that the third step changed 0.5mL of diethylene glycol dimethyl ether to 0.5mL of HPMe. The nuclear magnetic yield of chiral pyrrolo-imidazole ring formation is 97%, and ee is 90%.
Example 19
This example differs from example 1 in that the third step changed 0.5mL of diethylene glycol dimethyl ether to 0.5mL of LDMSO. The nuclear magnetic yield of chiral pyrrolo-imidazole ring formation is 78 percent, and ee is 94 percent.
Example 20
This example differs from example 1 in that the third step changed 0.5mL of diethylene glycol dimethyl ether to 0.5mL of DMMF. The nuclear magnetic yield of chiral pyrrolo-imidazole ring formation is 94 percent, and ee is 86 percent.
Example 21
This example differs from example 1 in that the third step changed 0.5mL of diethylene glycol dimethyl ether to 0.5mL of NMP. The nuclear magnetic yield of chiral pyrrolo-imidazole ring formation is 82 percent and ee is 91 percent.
Example 22
This example differs from example 1 in that the substrate consists of N- (2-carbonylpropyl)) The benzamide is changed into N- (2-carbonyl propyl) -4-nitrobenzamide, and the obtained cis-trans intermediate product is cyclized to obtain the product 1. Y is 83.4%, ee is 95%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ8.27(d,J＝8.0Hz,2H),7.97(d,J＝8.0Hz,2H),7.30(ddd,J＝24.3,14.3,7.4Hz,6H),4.41(t,J＝5.7Hz,1H),4.40–4.20(m,2H),3.21–3.08(m,1H),2.75–2.58(m,1H),1.98(s,3H).
example 23
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -2-naphthamide and product 2 was obtained by column chromatography. Y is 78% and ee is 93%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ8.21(s,1H),8.02(d,J＝8.6Hz,1H),7.95–7.79(m,3H),7.54–7.45(m,2H),7.41–7.31(m,2H),7.31–7.24(m,4H),4.47–4.35(m,2H),4.29(dt,J＝10.5,7.5Hz,1H),3.19–3.04(m,1H),2.63(dq,J＝15.0,7.5Hz,1H),2.02(s,3H).
example 24
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-biphenylcarboxamide and product 3 was obtained by column chromatography. Y is 79% and ee is 95%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.3Hz,2H),7.66(dd,J＝13.9,8.0Hz,4H),7.46(t,J＝7.6Hz,2H),7.36(t,J＝8.3Hz,3H),7.31–7.23(m,5H),4.44–4.30(m,2H),4.29–4.19(m,1H),3.18–3.05(m,1H),2.62(td,J＝15.0,7.5Hz,1H),2.01(s,3H).
example 25
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-methylbenzamide and in that the substrate was changed from cinnamaldehyde to 4-bromocinnamaldehyde. And (4) performing column chromatography to obtain a product 4. Y59%, ee 98%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.1Hz,2H),7.46(d,J＝8.3Hz,2H),7.23(d,J＝8.0Hz,2H),7.13(d,J＝8.3Hz,2H),4.38–4.22(m,2H),4.16(dt,J＝10.6,7.5Hz,1H),3.14–3.01(m,1H),2.52(td,J＝15.1,7.5Hz,1H),2.38(s,3H),1.96(s,3H).
example 26
The true bookThe example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-methylbenzamide and in that the substrate was changed from cinnamaldehyde to 4-phenylcinnamaldehyde. And (5) performing column chromatography to obtain a product. Y75%, ee 96%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.0Hz,2H),7.64–7.54(m,4H),7.44(t,J＝7.6Hz,2H),7.34(dd,J＝12.2,7.6Hz,3H),7.24(d,J＝8.1Hz,2H),4.42(t,J＝7.5Hz,1H),4.35–4.27(m,1H),4.24–4.12(m,1H),3.19–3.04(m,1H),2.61(tt,J＝20.7,10.2Hz,1H),2.39(s,3H),2.02(s,3H).
example 27
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-bromobenzamide and in that the substrate was changed from cinnamaldehyde to 4-methoxycinnamaldehyde. And performing column chromatography to obtain a product 6. Y65%, ee 94%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.3Hz,2H),7.53(d,J＝8.2Hz,2H),7.15(d,J＝8.2Hz,2H),6.87(d,J＝8.1Hz,2H),4.28(ddd,J＝18.5,13.6,5.9Hz,2H),4.21–4.10(m,1H),3.81(s,3H),3.06(td,J＝12.2,7.6Hz,1H),2.56(dq,J＝15.2,7.7Hz,1H),1.96(s,3H).
example 28
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-bromobenzamide and in that the substrate was changed from cinnamaldehyde to 3, 5-dichlorocinnamaldehyde. And (4) performing column chromatography to obtain a product 7. Y is 71%, ee is 92%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.8Hz,2H),7.55(d,J＝7.8Hz,2H),7.27(d,J＝3.7Hz,1H),7.12(s,2H),4.39–4.24(m,2H),4.17(dd,J＝17.6,7.7Hz,1H),3.19–3.06(m,1H),2.56(dq,J＝14.2,7.2Hz,1H),2.00(s,3H).
example 29
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-bromobenzamide and in that the substrate was changed from cinnamaldehyde to 3-nitrocinnamaldehyde. And (5) performing column chromatography to obtain a product 8. Y is 62%, ee is 94%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ8.14(s,2H),7.66(t,J＝8.5Hz,2H),7.62–7.48(m,4H),4.49(t,J＝7.6Hz,1H),4.36–4.16(m,2H),3.26–3.12(m,1H),2.69–2.54(m,1H),1.95(s,3H).
example 30
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-methylbenzamide. And (5) performing column chromatography to obtain a product 9. Y is 58% and ee is 95%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.7Hz,2H),7.42–7.29(m,2H),7.25(q,J＝7.7Hz,5H),4.41–4.31(m,1H),4.31–4.23(m,1H),4.23–4.10(m,1H),3.07(td,J＝12.4,7.6Hz,1H),2.58(td,J＝14.6,7.4Hz,1H),2.38(s,3H),1.97(s,3H).
example 31
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-bromobenzamide. And (5) performing column chromatography to obtain a product 10. Y72%, ee 95%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.1Hz,2H),7.58-7.48(m,2H),7.34(t,J＝7.3Hz,2H),7.25(dd,J＝15.1,8.1Hz,4H),4.36(t,J＝7.5Hz,1H),4.31-4.22(m,1H),4.14(dt,J＝19.6,9.8Hz,1H),3.15-3.03(m,1H),2.60(dq,J＝14.7,7.5Hz,1H),1.96(s,3H).
example 32
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-methoxybenzamide. And (5) performing column chromatography to obtain a product 11. Y is 50%, ee is 95%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.4Hz,2H),7.34(t,J＝7.3Hz,2H),7.30-7.20(m,5H),6.96(d,J＝8.4Hz,2H),4.36(t,J＝7.5Hz,1H),4.31-4.21(m,1H),4.20-4.09(m,1H),3.84(s,3H),3.15-3.00(m,1H),2.58(dq,J＝14.7,7.5Hz,1H),1.97(s,3H).
example 33
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-nitrobenzamide. The substrate is changed from cinnamaldehyde to 4-cyano cinnamaldehyde. And (4) performing column chromatography to obtain a product 12. Y is 70%, ee is 94%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ8.32-8.17(m,2H),7.95(d,J＝8.9Hz,2H),7.64(d,J＝8.2Hz,2H),7.36(d,J＝8.2Hz,2H),3.28-3.12(m,1H),2.63(td,J＝15.3,7.5Hz,1H),1.95(s,3H).
example 34
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-nitrobenzamide. The substrate is changed from cinnamaldehyde to 4-bromocinnamaldehyde. And performing column chromatography to obtain a product 13. Y74%, ee 97%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ8.26(d,J＝8.5Hz,2H),7.96(d,J＝8.5Hz,2H),7.47(d,J＝7.9Hz,2H),7.11(d,J＝7.9Hz,2H),4.38(dd,J＝14.2,7.7Hz,2H),4.27(dd,J＝17.7,7.8Hz,1H),3.16(td,J＝12.4,7.7Hz,1H),2.61(dq,J＝14.9,7.6Hz,1H),1.97(s,3H).
example 35
This example differs from example 1 in that the substrate was changed from cinnamaldehyde to 4-bromocinnamaldehyde. And performing column chromatography to obtain a product 14. Y is 49%, ee is 96%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.80(d,J＝7.4Hz,2H),7.50-7.39(m,4H),7.33(t,J＝7.4Hz,1H),7.13(d,J＝8.3Hz,2H),4.41-4.25(m,2H),4.19(dt,J＝10.7,7.5Hz,1H),3.09(dtd,J＝12.5,7.8,4.5Hz,1H),2.54(td,J＝15.2,7.5Hz,1H),1.97(s,3H).
example 36
This example differs from example 1 in that the substrate was changed from cinnamaldehyde to 4-methoxycinnamaldehyde. And (5) performing column chromatography to obtain a product 15. Y is 53%, ee is 97%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.80(d,J＝7.4Hz,2H),7.41(t,J＝7.6Hz,2H),7.30(dd,J＝14.1,6.7Hz,1H),7.16(d,J＝8.5Hz,2H),6.87(d,J＝8.5Hz,2H),3.80(s,3H),3.10-2.97(m,1H),2.54(td,J＝15.2,7.6Hz,1H),1.98(s,3H).
example 37
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-trifluoromethylbenzamide. And performing column chromatography to obtain a product 17. Y75%, ee 96%. The nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.2Hz,2H),7.69(dd,J＝20.3,6.4Hz,2H),7.40-7.31(m,2H),7.31-7.19(m,4H),4.43-4.28(m,2H),4.21(dt,J＝10.6,7.5Hz,1H),3.12(dtd,J＝12.7,7.8,4.5Hz,1H),2.62(ddd,J＝15.4,13.0,7.3Hz,1H),1.98(d,J＝0.6Hz,3H).
example 38
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -4-trifluoromethylbenzamide. The substrate is changed from cinnamaldehyde to 3-cyano cinnamaldehyde. And performing column chromatography to obtain a product 18. Y is 70.2%, ee is 97%. The nuclear magnetic data are as follows:1H NMR(600MHz,CDCl3)δ7.91(d,J＝8.1Hz,2H),7.65(t,J＝19.1Hz,2H),7.60-7.52(m,2H),7.51-7.42(m,2H),4.42(t,J＝7.6Hz,1H),4.37-4.30(m,1H),4.25(dt,J＝10.1,7.5Hz,1H),3.22-3.13(m,1H),2.66-2.53(m,1H),1.96(s,3H).
example 39
This example differs from example 1 in that the substrate was changed from cinnamaldehyde to 3- (6-chloropyridyl) acrolein. To obtain a product 19. HRMS (M + H)+)C18H17ClN3 +(ii) a Calculated value, 310.1106, measured value: 310.1103, respectively; the nuclear magnetic yield was 70%, and ee ═ 92%.
Example 40
This example differs from example 1 in that the substrate was changed from cinnamaldehyde to 3- (2-furyl) acrolein. To obtain the product 20. HRMS (M + H)+)C17H17N2O+(ii) a Calculated value, 265.1335, measured value: 265.1342, respectively; the nuclear magnetic yield was 65%, and ee ═ 94%.
EXAMPLE 41
This example differs from example 1 in that the substrate was changed from cinnamaldehyde to 3- (2-thienyl) acrolein. To obtain a product 21. HRMS (M + H)+)C17H17N2S+Exact masses: 281.1107; calculated value, 265.1335, measured value: 265.1342, respectively; the nuclear magnetic yield was 65%, and ee ═ 94%.
Example 42
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to 1-methyl-N- (2-oxopropyl) -1H-indolyl-3-carboxamide). To obtain the product 22. HRMS (M + H)+)C22H22N3 +Calculated value 328.1808; measurement values: 328.1810, respectively; nuclear magnetic yield57％，ee＝90％。
Example 43
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -2-pyridinecarboxamide. To obtain the product 23. HRMS (M + H)+)C18H18N3 +Calculated value 276.1495; measurement values: 276.1489, respectively; the nuclear magnetic yield was 38%, and ee ═ 90%.
Example 44
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (2-carbonylpropyl) -trifluoroacetamide. To obtain the product 24. HRMS (M + H)+)C14H14F3N2 +(ii) a Calculated value, 267.1104, measured value: 267.1109, respectively; nuclear magnetism 47%, ee 95%.
Example 45
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (3-methyl-2-carbonylbutyl) trifluoroacetamide and cinnamaldehyde to 3- (4-cyanophenyl) acrolein. To obtain a product 25. HRMS (M + H)+)C17H17F3N3 +(ii) a Calculated value, 320.1369, measured value: 320.1378, respectively; nuclear magnetism 37%, ee 92%.
Example 46
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to N- (3, 3-dimethyl-2-carbonylbutyl) trifluoroacetamide and cinnamaldehyde to 3- (3, 5-dichlorophenyl) acrolein. To obtain a product 26. HRMS (M + H)+)C17H18Cl2F3N2 +(ii) a Calculated value, 377.0794, measured value: 377.0786, respectively; nmr 30%, ee 94%.
Example 47
This example differs from example 1 in that the substrate was changed from N- (2-carbonylpropyl) benzamide to 3-trifluoroacetylacetophenone. To obtain a product 27. HRMS (M + H)+)C19H16F3N2 +(ii) a Calculated value, 329.1260, measured value: 329.1253, respectively; the nuclear magnetic yield was 65%, and ee ═ 97%.
The above description is only for the purpose of creating a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can substitute or change the technical solution and the inventive concept of the present invention within the technical scope of the present invention.
Claims (9)
1. A synthetic method of chiral pyrroloimidazole compounds is characterized in that the synthetic method of chiral pyrroloimidazole compounds; under the action of a chiral secondary amine catalyst and an additive, the alpha-aminoketone and alpha, beta-unsaturated aldehyde are subjected to three-step reaction of asymmetric cyclization, selective hydroxyl reduction and racemization-free ring closure to prepare a compound with a chiral pyrroloimidazole structure shown in a general formula I;
the first step is as follows: asymmetric cyclization; in a proper solvent, alpha-aminoketone (compound A) and alpha, beta-unsaturated aldehyde (compound B) are subjected to one-step cyclization reaction under the action of a chiral secondary amino catalyst and an additive to obtain a compound C;
the second step is that: selective hydroxyl reduction; dehydrating and reducing the compound C to obtain a diastereoisomer mixture, namely a compound D;
the third step: no racemization closed ring; the compound D is subjected to further cyclization aromatization to obtain a compound with a chiral pyrroloimidazole structure shown in a general formula I;
wherein: r1Is C6-C20Any one of alkylphenyl, alkoxyphenyl, carboxylate phenyl, halophenyl, nitrophenyl, cyanophenyl, biphenyl, naphthyloxyphenyl, trifluoromethylphenyl, trichloromethylphenyl, and trifluoromethoxyphenyl, or di-or tri-substituted phenyl with the above functional group at different positions; ferrocenyl; 2-thienyl, 3-thienyl; 2-furyl group, 3-furyl group; 2 positionPyridyl substituted at the 3 or 4 position; n-methyl-3, 4 or 5-indolyl; including perfluorocarboxyalkyl (Rf) groups containing 1 to 10 carbons;
R2is C1-C6Alkyl of (C)6-C20Any one of alkyl phenyl, alkoxy phenyl, halogenated phenyl, nitro phenyl, nitrile phenyl, biphenyl, naphthoxy phenyl, trifluoromethyl phenyl, trichloromethyl phenyl and trifluoromethoxyphenyl, or disubstituted or trisubstituted phenyl with functional groups at different positions on the benzene ring;
R3is C6-C20Any one of alkylphenyl, alkoxyphenyl, carboxylate phenyl, halophenyl, nitrophenyl, cyanophenyl, biphenyl, naphthyloxyphenyl, trifluoromethylphenyl, trichloromethylphenyl, and trifluoromethoxyphenyl, or di-or tri-substituted phenyl with the above functional group at different positions; ferrocenyl; 2-thienyl, 3-thienyl; 2-furyl group, 3-furyl group; pyridyl substituted at the 2-, 3-or 4-position; n-methyl-3, 4 or 5-indolyl.
2. The synthesis method according to claim 1, wherein the specific synthesis method is as follows: 0.1 to 50mol percent of chiral secondary amine catalyst and 0 to 50mol percent of additive are mixed, dissolved by organic solvent, stirred for 30min and added with 1 equivalent of alpha, beta-unsaturated aldehyde and 1.1 equivalent of alpha-aminoketone (A); reacting for 24 hours at the temperature of minus 10-40 ℃, adding dichloromethane, adding triethylsilane, trifluoroacetic acid, and carrying out ice-alcohol bath overnight; monitoring by TLC: P/E3/1, reaction was complete. Performing column chromatography to obtain a product; accurately weighing the product obtained by column chromatography, adding a cyclization solvent, adding 0-10 mol% of an acidic additive, and monitoring the completion of the reaction by TLC (thin layer chromatography) at 100 ℃ by 1-50 times of ammonium salt; and (4) performing column chromatography to obtain a product.
3. A synthesis method according to claim 1, characterized in that in the first step, the chiral catalyst is α, α -diphenylprolinol trimethylsilylether or α, α -bis- (3,5) -bistrifluoromethylphenylprolinol trimethylsilylether.
4. The method of claim 1, wherein in the first step, the additive is either no additive or C2-C6Alkyl carboxylic acid of (2), C2-C6Alkyl sulfonic acid, C6-C20Aryl sulfonic acid, binaphthol phosphonic acid, C7-C10 substituted benzoic acid and polyacrylic acid, potassium acetate, triethylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene, 1, 5-diazabicyclo [4.3.0]Non-5-ene, 7-methyl-1, 5, 7-triazabicyclo [4.4.0]Dec-5-ene, 1, 4-diazabicyclo [2.2.2]Octane, triazabicyclo, Tetramethylguanidine (TMG).
5. The synthesis process according to claim 1, characterized in that in the first step, the preferred additive is benzoic acid.
6. The method of claim 1, wherein in the first step, the solvent is at least one of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, ethyl acetate, benzene, toluene, acetone, acetonitrile, diethyl ether, methanol, ethanol, DMF, DMSO, and NMP.
7. The method according to claim 1, wherein the reaction solvent in the cyclized aromatization in the third step is at least one of acetonitrile, acetone, trifluoroacetic acid, acetic acid, diglyme, DMF, DMAC, HMP, DMI, DMSO, and NMP.
8. The synthesis method according to claim 1, wherein the ammonia source in the cyclized aromatization in the third step is at least one of ammonium sulfate, ammonium bisulfate, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium fluoride, ammonium bromide, ammonium iodide, ammonium acetate, a methanol solution of ammonia, and ammonia water.
9. The synthesis method according to claim 1, wherein in the third step of cyclized aromatization, the additive is not added or is one of acetic acid, formic acid, trifluoroacetic acid, propionic acid and benzoic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110720046.0A CN114105993B (en) | 2021-06-28 | 2021-06-28 | Synthesis method of chiral pyrroloimidazole compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110720046.0A CN114105993B (en) | 2021-06-28 | 2021-06-28 | Synthesis method of chiral pyrroloimidazole compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114105993A true CN114105993A (en) | 2022-03-01 |
| CN114105993B CN114105993B (en) | 2023-03-10 |
Family
ID=80359373
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110720046.0A Active CN114105993B (en) | 2021-06-28 | 2021-06-28 | Synthesis method of chiral pyrroloimidazole compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114105993B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942553A (en) * | 2019-04-17 | 2019-06-28 | 大连理工大学 | A kind of synthesis of tri- substituted-tetrahydro 2H- pyran-2-one compound of chirality 3,4,6- and its method for transformation |
| CN110734456A (en) * | 2019-11-06 | 2020-01-31 | 南京谷睿生物科技有限公司 | compounds, preparation method and medical application thereof |
-
2021
- 2021-06-28 CN CN202110720046.0A patent/CN114105993B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942553A (en) * | 2019-04-17 | 2019-06-28 | 大连理工大学 | A kind of synthesis of tri- substituted-tetrahydro 2H- pyran-2-one compound of chirality 3,4,6- and its method for transformation |
| CN110734456A (en) * | 2019-11-06 | 2020-01-31 | 南京谷睿生物科技有限公司 | compounds, preparation method and medical application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 许海童: "保护基控制的(2,3)-反式手性吡咯烷类化合物的合成研究", 《大连理工大学硕士学位论文》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114105993B (en) | 2023-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bai et al. | Quinine-catalyzed asymmetric domino Mannich-cyclization reactions of 3-isothiocyanato oxindoles with imines for the synthesis of spirocyclic oxindoles | |
| US9221744B2 (en) | Asymmetric catalysts | |
| Zhu et al. | Catalytic asymmetric homo-1, 3-dipolar cycloadditions of azomethine ylides: diastereo-and enantioselective synthesis of imidazolidines | |
| Li et al. | One-pot, highly efficient, asymmetric synthesis of ring-fused piperidine derivatives bearing N, O-or N, N-acetal moieties | |
| Kojima et al. | Asymmetric synthesis of activated cyclopropanes catalyzed by cinchonidine as a chiral Brønsted base | |
| CN109734600B (en) | Synthesis method of chiral beta-hydroxy acid ester compound | |
| Abdellaoui et al. | Versatile synthesis of 4-spiro-β-lactam-3-carbonitriles via the intramolecular nucleophilic cyclization of N-(p-hydroxyphenyl) cyanoacetamides | |
| Mahmud et al. | An intramolecular azomethine ylide–alkene cycloaddition approach to pyrrolo [3, 2-c] quinolines-synthesis of a C2-truncated martinelline model | |
| CN104689849B (en) | One class phosphamide (primary) secondary amine bifunctional catalyst and its synthetic method | |
| CN111592507A (en) | Novel green and simple method for preparing polysubstituted furan | |
| JP7464234B2 (en) | Method for producing highly optically active allene carboxylic acid compounds having axial asymmetry | |
| Luo et al. | Asymmetric synthesis of O-alkylated tetronic acid derivatives via an organocatalytic Mannich reaction and subsequent intramolecular cyclization | |
| CN114105993B (en) | Synthesis method of chiral pyrroloimidazole compound | |
| Zhang et al. | Enantioselective conjugate addition of 1-bromonitroalkanes to α, β-unsaturated aldehydes catalyzed by chiral secondary amines | |
| Chen et al. | Highly stereoselective synthesis of trans-4-trifluoromethylsulfonyl-2, 3-dihydrofurans from arsonium ylides and (E)-α-trifluoromethylsulfonyl-α, β-unsaturated ketones | |
| Benedetti et al. | Intramolecular ring opening of epoxides by bis-activated carbanions. The influence of ring size on reactivity and selectivity | |
| CN108484500B (en) | Preparation method of 1-trifluoroethyl isoquinoline | |
| CN114716361B (en) | Method for synthesizing chiral spiro indenone-pyrrole compound | |
| Licheng et al. | Exploration of Quinim Ligand in Ni-Catalyzed Enantioselective Reductive Carbamoyl-Alkylation of Alkene | |
| CN111499542B (en) | Preparation method of cyclic ketene compound containing alpha-cyano substituted quaternary carbon center | |
| CN111170926B (en) | Method for catalyzing asymmetric synthesis of chiral beta-alkynyl-beta-aminoketone derivative | |
| CN109942553B (en) | Synthesis and conversion method of chiral 3,4, 6-trisubstituted tetrahydro 2H-pyran-2-one compound | |
| JP4283043B2 (en) | Process for producing stereoisomer-enriched 4-aryl-4-hydroxybutanoic acid derivatives | |
| CN112500419A (en) | Epoxy fused 2-methylene pyrrolidine compound and preparation method thereof | |
| CN107721917B (en) | Green synthesis method of polysubstituted nicotinate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |