CN111269097B - Synthesis method of polycyclic disubstituted 1, 3-propanedione compound - Google Patents
Synthesis method of polycyclic disubstituted 1, 3-propanedione compound Download PDFInfo
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Abstract
The invention relates to a synthesis method of a multi-ring disubstituted 1, 3-propanedione compound, wherein the structural formula of the 1, 3-propanedione compound is shown as a formula I, the synthesis method comprises the step of reacting a compound shown as a formula II with a compound shown as a formula III at 10-30 ℃ in the presence of amino potassium and tetrahydrofuran under the protection of inert gas to obtain the compound shown as the formula I, and the structural formula of the compound shown as the formula I is as follows:
the structural formula of the compound shown in the formula II is as follows:
(ii) a The structural formula of the compound shown in the formula III is as follows:
wherein R is 1 、R 2 Independently selected from C3-C6 cycloalkyl. The synthesis method disclosed by the invention adopts the amino potassium as the condensation accelerator, is beneficial to promoting the reaction, safe and efficient in reaction, not easy to flash explosion, easy to operate and synthesize, and mild in reaction temperature by matching with tetrahydrofuran as a solvent, can reduce the reaction energy consumption, is simple and efficient in reaction, and is more suitable for industrial production. Compared with the existing synthesis method, the method is milder and easy to operate.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for synthesizing a polycyclic disubstituted 1, 3-propanedione compound.
Background
The 1, 3-propanedione compound disubstituted with polycyclic rings is an important medical intermediate, such as a synthetic intermediate used for synthesizing herbicides, and has wide application in the field of medical chemistry.
As for the synthesis of 1, 3-propanediones, they are mostly prepared by condensation of ketones with esters, whereas for the condensation of polycyclic substituted ketones with polycyclic substituted esters, the condensation of polycyclic substituted ketones with polycyclic substituted esters in the presence of sodium hydride and organic solvents is currently common, as in the references: sawa M, dr. Kazuhiro Morisaki, kondo Y, et al, direct Access to N-Un protected α -and/or β -TetraSubstited Amino Acid acids Esters via Direct catalysis-Type Reactions Using N-Un protected Trifluoromethyl ketones [ J ].2017,23 (67).
However, sodium hydride is used in the synthesis method to participate in the reaction, hydrogen is easily generated in the reaction process, and the synthesis method is easy to flash and explode, is unsafe, has high requirements on the operation level of experimenters, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a safe and effective synthetic method of a multi-ring disubstituted 1, 3-propanedione compound which is not easy to flash, simple and convenient to operate and high in efficiency.
In order to achieve the purpose, the invention adopts the technical scheme that:
a synthesis method of 1, 3-propanedione compound with multiple ring disubstituted is disclosed, the structural formula of the 1, 3-propanedione compound is shown in formula I,
the synthesis method comprises the step of reacting a compound shown as a formula II with a compound shown as a formula III in the presence of potassium amide and tetrahydrofuran at 10-30 ℃ under the protection of inert gas to obtain the compound shown as the formula I,
the structural formula of the compound shown in the formula II is as follows:
the structural formula of the compound shown in the formula III is as follows:
wherein R is 1 、R 2 Independently selected from C3-C6 cycloalkyl.
Preferably, the compound of formula I is 1, 3-dicyclohexyl-1, 3-propanedione, 1, 3-dicyclopentyl-1, 3-propanedione, 1, 3-dicyclobutyl-1, 3-propanedione, 1, 3-dicyclopropyl-1, 3-propanedione, 1-cyclohexyl-3-cyclopentyl-1, 3-propanedione, 1-cyclohexyl-3-cyclobutyl-1, 3-propanedione, 1-cyclohexyl-3-cyclopropyl-1, 3-propanedione, 1-cyclopentyl-3-cyclobutyl-1, 3-propanedione, 1-cyclopentyl-3-cyclopropyl-1, 3-propanedione or 1-cyclobutyl-3-cyclopropyl-1, 3-propanedione.
According to a further embodiment of the invention, the reaction temperature of the reaction is between 20 and 30 ℃.
According to a further embodiment of the present invention, the reaction time of the reaction is 3 to 4 hours.
According to a further embodiment of the invention, R is 1 、R 2 Are selected from the same cycloalkyl groups.
According to a further embodiment of the present invention, the feeding molar ratio of the compound represented by the formula II to the compound represented by the formula III is 1.2 to 2:1.
according to a further embodiment of the invention, the molar ratio of the charged amino potassium to the compound of formula III is 1.5 to 2.5.
According to a further embodiment of the invention, the synthesis method comprises the steps of:
(1) Under the protection of inert gas, dissolving the compound shown in the formula II and the compound shown in the formula III in tetrahydrofuran, then adding amino potassium, and stirring and reacting for 3-4 h at the temperature of 20-30 ℃ to obtain reaction liquid;
(2) Pouring the reaction liquid prepared in the step (1) into ice water, adding ether for layering, firstly adjusting the pH of a water layer to be less than 7, then adjusting the pH of the water layer to be more than 7, extracting with ether, drying, removing a solvent, carrying out chromatography purification, and eluting to obtain the compound shown in the formula I.
Preferably, in step (2), the pH of the aqueous layer is adjusted to 4.0 to 5.5 with HCl, and then Na is added 2 CO 3 The pH of the aqueous layer is adjusted to 7.5-8.
Preferably, in the step (2), the drying is performed by using anhydrous magnesium sulfate.
Preferably, in the step (2), the elution is carried out by using a mixed solution of dichloromethane and methanol in a volume ratio of 15-25.
The compound shown in the formula I synthesized by the synthesis method is applied to the fields of synthesis and medicinal chemistry.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the synthesis method disclosed by the invention adopts the amino potassium as the condensation accelerator, is beneficial to promoting the reaction, safe and efficient in reaction, not easy to flash explosion, easy to operate and synthesize, and mild in reaction temperature by matching with tetrahydrofuran as a solvent, can reduce the reaction energy consumption, is simple and efficient in reaction, and is more suitable for industrial production. Compared with the existing synthesis method, the method is milder and easy to operate.
Detailed Description
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are provided merely to further illustrate the invention and are not intended to limit the scope of the invention in any way.
The starting materials may be obtained from commercial sources, or prepared by methods known in the art, or prepared according to the methods described herein.
The structure of the compound is determined by nuclear magnetic resonance 1 H-NMR)、( 13 C-NMR and/or Mass Spectrometry (MS). NMR was measured using an ACF-400BRUK type nuclear magnetic resonance spectrometer using deuterated chloroform (CDCl) as a solvent 3 ) Or deuterated dimethyl sulfoxide (DMSO-D) 6 ) TMS is an internal standard. The column chromatography adopts 200-300 mesh silica gel (produced by Qingdao ocean chemical plant).
Example 1
Synthesis of 1, 3-dicyclohexyl-1, 3-propanedione
1-cyclohexyl-1-ethanone (18.9g, 150mmol,) and methyl cyclohexanecarboxylate (14.2g, 100mmol) were dissolved in 80mL of anhydrous tetrahydrofuran under nitrogen protection, and potassium amino (11.0 g, 200mmol) was added and the reaction was stirred at room temperature (23 ℃ C.) for 3.5h. After the reaction is finished, pouring the reaction liquid into ice water, and adding BThe ether was separated and the aqueous layer was adjusted to pH =5.0 with 2N HCl and Na 2 CO 3 Adjusted to pH =7.5, extracted with ether and dried over anhydrous magnesium sulfate. Most of the solvent was removed by rotation, and purified by silica gel column chromatography eluting with methylene chloride/methanol (V/V = 20/1) to give 1, 3-dicyclohexyl-1, 3-propanedione (19.9 g). Yield: 84 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ15.75(br,1H),5.49(s,1H),2.21-2.14(m,2H),1.88-1.79(m,8H),1.73-1.68(m,2H),1.41-1.17(m,10H).
example 2
Synthesis of 1, 3-dicyclopentyl-1, 3-propanedione
In this example, the raw materials used were 1-cyclopentyl-1-ethanone and methyl cyclopentanoate, the molar ratio of 1-cyclopentyl-1-ethanone to methyl cyclopentanoate was 1.5: 85 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ15.66(br,1H),5.56(m,1H),2.59(m,1H),2.44(m,1H),1.79-1.76(m,3H),1.74(m,1H),1.70-1.65(m,10H).
13 C NMR(125MHz,CDCl 3 )δ205.00(d),54.62(dt),51.13(dtd),28.91(dt),25.50(td).
example 3
Synthesis of 1, 3-dicyclobutyl-1, 3-propanedione
The raw materials adopted in this example are 1-cyclobutyl-1-ethanone and methyl cyclobutanecarboxylate, the charging molar ratio of 1-cyclobutyl-1-ethanone to methyl cyclobutanecarboxylate is 1.5: 85 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ5.56(d,1H),2.67(m,1H),2.47(m,1H),1.99-1.94(m,8H),1.76-1.73(m,4H).
13 C NMR(125MHz,CDCl 3 )δ205.08(d),55.10(dt),47.45(dh),28.07(t),20.56(dt).
example 4
Synthesis of 1, 3-dicyclopropyl-1, 3-propanedione
In this example, the raw materials adopted were 1-cyclopropane-1-ethanone and methyl cyclopropanecarboxylate, the molar ratio of the 1-cyclopropane-1-ethanone to the methyl cyclopropanecarboxylate was 1.5, and the following examples were repeated to prepare 1, 3-dicyclopropyl-1, 3-propanedione, with the following yields: 83 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ5.58(d,1H),2.20(pd,1H),2.03(p,1H),1.45-1.40(m,4H),
0.82-0.79(m,4H).
13 C NMR(125MHz,CDCl 3 )δ201.53(d),57.47(dt),23.09(h),8.92(d).
example 5
Synthesis of 1-cyclohexyl-3-cyclopentyl-1, 3-propanedione
In this example, the raw materials used were 1-cyclohexyl-1-ethanone and methyl cyclopentanoate, the molar ratio of 1-cyclohexyl-1-ethanone to methyl cyclopentanoate charged was 1.5, and 1-cyclohexyl-3-cyclopentyl-1, 3-propanedione was finally prepared in the same manner as in example 1, with the following yields: 65 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ3.27(s,2H),2.60(p,1H),2.50(p,1H),1.74(m,13H),1.56(m,5H),1.48(m,2H).
13 C NMR(125MHz,CDCl 3 )δ206.67(d),205.00(d),54.80(dt),51.08(qt),48.38(dqt),31.78(dt),29.54(dt),26.35(tt),25.41(m).
example 6
Synthesis of 1-cyclohexyl-3-cyclobutyl-1, 3-propanedione
In this example, the raw materials used were 1-cyclohexyl-1-ethanone and methyl cyclobutanecarboxylate, the molar ratio of the 1-cyclohexyl-1-ethanone to the methyl cyclobutanecarboxylate was 1.5, and the following procedure was repeated in the same manner as in example 1 to obtain 1-cyclohexyl-3-cyclobutyl-1, 3-propanedione, with the following yields: 62 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ3.28(s,2H),2.62(p,1H),2.50(p,1H),2.10(dq,2H),1.98(dq,2H),1.73(m,6H),1.56(m,4H),1.49(m,2H).
13 C NMR(125MHz,CDCl 3 )δ206.67(d),205.25(d),55.20(dt),48.42(dqt),47.38(tt),31.52(dt),28.13(t),26.38(tt),25.32(dt),20.40(dt).
example 7
Synthesis of 1-cyclohexyl-3-cyclopropyl-1, 3-propanedione
In this example, the raw materials used were 1-cyclohexyl-1-ethanone and methyl cyclopropanecarboxylate, the molar ratio of 1-cyclohexyl-1-ethanone to methyl cyclopropanecarboxylate was 1.5, and other examples were the same as in example 1, and 1-cyclohexyl-3-cyclopropyl-1, 3-propanedione was finally obtained with the following yields: 61 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ3.31(s,2H),2.50(p,1H),2.22(p,1H),1.73(m,4H),1.58(m,2H),1.55(m,4H),1.46(m,1H),1.07(m,4H).
13 C NMR(125MHz,CDCl 3 )δ206.67(d),202.82(d),57.19(dt),48.38(dqt),31.52(dt),26.38(tt),25.23(dt),22.99(q),8.91(d).
example 8
Synthesis of 1-cyclopentyl-3-cyclobutyl-1, 3-propanedione
In this example, the raw materials adopted are 1-cyclopentyl-1-ethanone and methyl cyclobutanecarboxylate, the charging molar ratio of 1-cyclopentyl-1-ethanone to methyl cyclobutanecarboxylate is 1.5: and 64 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ3.28(s,2H),2.64(dp,2H),2.10(dq,2H),1.96(dq,2H),1.75(m,10H).
13 C NMR(125MHz,CDCl 3 )δ205.25(d),205.00(d),55.20(dt),51.08(dqt),47.22(tt),29.08(dt),28.07(t),25.48(td),20.64(dt).
example 9
Synthesis of 1-cyclopentyl-3-cyclopropyl-1, 3-propanedione
In this example, the raw materials used were 1-cyclopentyl-1-ethanone and methyl cyclopropanecarboxylate, the molar ratio of 1-cyclopentyl-1-ethanone to methyl cyclopropanecarboxylate was 1.5, and the following examples were repeated in the same manner as in example 1 to obtain 1-cyclopentyl-3-cyclopropyl-1, 3-propanedione, with the following yields: 59 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ3.31(s,2H),2.67(p,1H),2.23(p,1H),1.80(m,4H),1.68(m,1H),1.66(ddt,3H),1.08(m,4H).
13 C NMR(125MHz,CDCl 3 )δ204.58(d),201.55(d),57.19(dt),51.24(dqt),29.08(dt),25.47(td),23.25(m),8.91(d)
example 10
Synthesis of 1-cyclobutyl-3-cyclopropyl-1, 3-propanedione
In this example, the raw materials adopted were 1-cyclobutyl-1-ethanone and methyl cyclopropanecarboxylate, the molar ratio of the 1-cyclobutyl-1-ethanone to the methyl cyclopropanecarboxylate was 1.5, and the following procedure was repeated in the same manner as in example 1 to finally obtain 1-cyclobutyl-3-cyclopropyl-1, 3-propanedione, with the following yields: 58 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ3.31(s,2H),2.63(p,1H),2.23(p,1H),2.11(dq,2H),1.95(dq,2H),1.75(q,2H),1.08(m,4H).
13 C NMR(125MHz,CDCl 3 )δ205.06(d),201.55(d),57.05(dt),47.40(dp),28.07(t),23.18(dt),20.04(dt),8.88(d).
comparative example 1
This comparative example allows the reaction to be carried out in DMSO as follows:
1-cyclohexyl-1-ethanone (18.9g, 150mmol,) and methyl cyclohexanecarboxylate (14.2g, 100mmol) were dissolved in 80mL of DMSO under nitrogen protection, and potassium amino (11.0 g, 200mmol) was added and the reaction stirred at room temperature for 3.5h. After the reaction, the reaction mixture was poured into ice water, and the ether solution was added to separate layers, and the aqueous layer was adjusted to pH =5.0 with 2N HCl, and then Na was added 2 CO 3 Adjusted to pH =7.5, extracted with ether and dried over anhydrous magnesium sulfate. Most of the solvent was removed by rotation, and purified by silica gel column chromatography using methylene chloride/methanol (V/V = 20/1) to give 1, 3-dicyclohexyl-1, 3-propanedione (17.1 g). Yield: 72 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ15.75(br,1H),5.50(s,1H),2.22-2.14(m,2H),1.88-1.79(m,8H),1.73-1.68(m,2H),1.41-1.17(m,10H).
13 C NMR(125MHz,CDCl 3 )δ206.67(m),42.15(m),26.35(tt),25.23(dt).
comparative example 2
This comparative example allows the reaction to be carried out in xylene solvent as follows:
under nitrogen protection, 1-cyclohexyl-1-ethanone (18.9g, 150mmol) and methyl cyclohexanecarboxylate (14.2g, 100mmol) were dissolved in 80mL of xylene, and potassium amino (11.0 g, 200mmol) was added, and the reaction was stirred at room temperature for 3.5h. After the reaction, the reaction solution was poured into ice water, and the ether solution was added thereto to layer, and the aqueous layer was adjusted to pH =5.0 with 2N HCl, and then Na was added thereto 2 CO 3 Adjusted to pH =7.5, extracted with ether and dried over anhydrous magnesium sulfate. Most of the solvent was removed by rotation, and purified by silica gel column chromatography using methylene chloride/methanol (V/V = 20/1) to give 1, 3-dicyclohexyl-1, 3-propanedione (14.2 g). Yield: 60 percent.
And (3) nuclear magnetic detection results:
1 H NMR(400MHz,CDCl 3 )δ15.73(br,1H),5.49(s,1H),2.21-2.14(m,2H),1.88-1.79(m,8H),1.73-1.68(m,2H),1.41-1.18(m,10H).
13 C NMR(125MHz,CDCl 3 )δ206.66(m),42.15(m),26.35(tt),25.24(dt).
the above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered in the protection scope of the present invention.
Claims (1)
1. A method for synthesizing 1, 3-dicyclohexyl-1, 3-propanedione, wherein the structural formula of the 1, 3-dicyclohexyl-1, 3-propanedione is as follows:
the method is characterized in that: under the protection of nitrogen, dissolving 150mmol of 1-cyclohexyl-1-ethanone and 100mmol of methyl cyclohexanecarboxylate in 80mL of anhydrous tetrahydrofuran, adding 200mmol of amino potassium, stirring at 23 ℃ for reacting for 3.5h, pouring the reaction solution into ice water after the reaction is finished, adding diethyl ether for layering, adjusting the pH of the water layer with 2N HCl to be =5.0, and then adding Na 2 CO 3 Adjusting to pH =7.5, extracting with ether, drying over anhydrous magnesium sulfate, removing the solvent by centrifugation, and purifying by silica gel column chromatography using dichloromethane/methanol at a volume ratio of 20/1 to obtain 1, 3-dicyclohexyl-1, 3-propanedione.
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| CN1259113A (en) * | 1997-06-03 | 2000-07-05 | 伊斯曼化学公司 | Process for the preparation of 1,3-dicarbonyl compounds |
| CN101304974A (en) * | 2005-11-08 | 2008-11-12 | 辉瑞有限公司 | Pyrazole derivatives and their medical use |
| WO2008047224A1 (en) * | 2006-10-19 | 2008-04-24 | Pfizer Limited | Pyrazolyl-4-oxy-benzonitrile derivatives useful in treating endometriosis |
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