CN112500345B - Synthetic method of alpha-cyano quaternary carbon substituted tetrahydroisoquinoline compound - Google Patents
Synthetic method of alpha-cyano quaternary carbon substituted tetrahydroisoquinoline compound Download PDFInfo
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Abstract
The invention belongs to the field of organic synthesis, and discloses a synthesis method of an alpha-cyano quaternary carbon substituted tetrahydroisoquinoline compound. The method has the advantages of simple and practical operation, mild reaction conditions and high yield and purity of the obtained product. The method is suitable for synthesizing isoquinoline compounds, in particular to the synthesis of alpha-cyano quaternary carbon substituted tetrahydroisoquinoline compounds.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a synthetic method of isoquinoline compounds, in particular to a synthetic method of alpha-cyano quaternary carbon substituted tetrahydroisoquinoline compounds.
Background
In the prior art, tetrahydroisoquinoline compounds are widely existed in natural products and bioactive molecules as an important organic amine compound. Chiral tetrahydroisoquinoline alkaloid has excellent bioactivity, is also an important medicine intermediate and is closely related to the life activity of human body. Wherein, the C-1 quaternary carbon substituted tetrahydroisoquinoline compound has rich biological activity. For example, the quaternary carbon-substituted tetrahydroisoquinoline compound MK-801 at C-1, also known as dezociclopine/diniconine (dizocilpine), belongs to a potent and highly selective NMDA (N-methyl-D-aspartic acid) receptor antagonist, and has anesthetic, anticonvulsant and antiepileptic effects as a central nervous system drug. Secondly, the derivative DNLCA of the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline is a non-competitive dopamine beta-hydroxylase inhibitor, has an important effect on controlling epinephrine synthesis, and can be used as a blood pressure lowering medicine; the derivative NLCA is detected in urine of a Parkinson patient treated by levodopamine, cerebellum and urine of a mouse, and has an important effect in treating Parkinson diseases. In addition, a large number of researches show that the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline compound has rich physiological activity and is an important potential central nervous system medicament.
However, the synthesis of α -cyanoquaternary carbon-substituted tetrahydroisoquinolines has not been widely studied, and only a few examples have been reported. The synthesis of the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline is realized mainly by two ways: one is through classical Lewis acid catalyzed Pictet-Spengler cyclization reaction, directly construct the skeleton of the tetrahydroisoquinoline and synthesize 1, 1-disubstituted tetrahydroisoquinoline; the second method is based on the existing tetrahydroisoquinoline skeleton compound, the C1 site proton is extracted under the alkaline condition, and the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline is synthesized through electrophilic substitution or electrophilic addition reaction.
Although the synthesis research of the alpha-cyano quaternary carbon-substituted tetrahydroisoquinoline has made a certain research progress, there still exist some problems, for example, the reaction conditions are harsh, the substrate application range is narrow, the introduction and removal of the protective agent makes the reaction process complicated and by-products increase, and the like, so that the research of an efficient synthesis method for synthesizing the alpha-cyano quaternary carbon-substituted tetrahydroisoquinoline compound has important research value and practical significance.
Disclosure of Invention
In order to solve the above disadvantages in the prior art, the present invention aims to provide a method for synthesizing alpha-cyano quaternary carbon substituted tetrahydroisoquinoline, so as to achieve the purpose of synthesizing alpha-cyano quaternary carbon substituted tetrahydroisoquinoline by using reaction conditions which are simple and convenient to operate, mild and environment-friendly.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
adding isoquinoline compounds into an organic solvent, adding methyl iodide, heating, carrying out salification activation, cooling to room temperature, adding a cyano source, a fluorine reagent and alkali, carrying out addition reaction to obtain the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline,
the chemical reaction formula is as follows:
wherein R is an alkane having 1 to 6 carbon atomsA group; r1And R2Are respectively-H and-CH3or-OCH3；Rxis-F, -Cl, -CH3and-OCH3One or two of them;
as a limitation of the present invention, the organic solvent is dichloromethane, 1, 2-dichloroethane, dioxane, toluene or methanol;
as another limitation of the invention, the cyano source is trimethylsilyl cyanide; the molar ratio of the cyano source to the isoquinoline compound is 1-2: 1;
as a third definition of the invention, the fluorine reagent is sodium fluoride or potassium fluoride; the molar ratio of the fluorine reagent to the isoquinoline compound is 1-2: 1;
as a fourth limitation of the present invention, the base is sodium carbonate, lithium carbonate, potassium phosphate, or triethylamine; the molar ratio of the alkali to the isoquinoline compound is 0.34-1: 1;
as a fifth limitation of the present invention, the heating reaction temperature is 30 to 80 ℃, and the reaction time is 30 to 60 min;
as a further limitation of the invention, the addition reaction time is 24-48 h;
due to the adoption of the technical scheme, compared with the prior art, the invention has the following beneficial effects:
(1) the synthesis method of the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline provided by the invention can be directly realized by the in-situ reaction of isoquinoline compounds, and the reaction operation is convenient and practical;
(2) the synthesis method of alpha-cyano quaternary carbon substituted tetrahydroisoquinoline provided by the invention adds a fluorine reagent in the addition reaction process, so that the nucleophilic reaction activity of a cyano source can be increased;
(3) the synthesis method of the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline provided by the invention has the advantages of mild reaction conditions, high activity, easy separation of the product and highest yield of the obtained target product reaching 99%;
in conclusion, the synthesis method of the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline provided by the invention can simply and effectively control the reaction process, separate the product and improve the yield of the target product;
the method is suitable for synthesizing isoquinoline compounds, and is particularly suitable for synthesizing alpha-cyano quaternary carbon substituted tetrahydroisoquinoline.
Drawings
FIG. 1 and FIG. 2 are a hydrogen nuclear magnetic spectrum and a carbon nuclear magnetic spectrum, respectively, of 1-phenyl-1-cyano-2-methyl-1, 2,3, 4-tetrahydroisoquinoline prepared in example 1 of the present invention;
FIG. 3 and FIG. 4 are a hydrogen nuclear magnetic spectrum and a carbon nuclear magnetic spectrum, respectively, of 1-cyano-2-methyl-1- (3-tolyl) -1,2,3, 4-tetrahydroisoquinoline prepared in example 12 of the present invention;
FIG. 5 and FIG. 6 are a hydrogen nuclear magnetic spectrum and a carbon nuclear magnetic spectrum, respectively, of 1-cyano-2-methyl-1- (4-tolyl) -1,2,3, 4-tetrahydroisoquinoline prepared in example 13 of the present invention;
FIG. 7 and FIG. 8 are a hydrogen nuclear magnetic spectrum and a carbon nuclear magnetic spectrum, respectively, of 1-cyano-2-methyl-1- (4-chlorophenyl) -1,2,3, 4-tetrahydroisoquinoline prepared in example 14 of the present invention;
FIG. 9, FIG. 10 and FIG. 11 are a hydrogen nuclear magnetic spectrum, a carbon nuclear magnetic spectrum and a fluorine nuclear magnetic spectrum, respectively, of 1-cyano-2-methyl-1- (4-fluorophenyl) -1,2,3, 4-tetrahydroisoquinoline prepared in example 15 of the present invention;
FIG. 12 and FIG. 13 are a hydrogen nuclear magnetic spectrum and a carbon nuclear magnetic spectrum, respectively, of 1-cyano-2-methyl-1- (4-methoxyphenyl) -1,2,3, 4-tetrahydroisoquinoline prepared in example 16 of the present invention;
FIG. 14 and FIG. 15 are a hydrogen nuclear magnetic spectrum and a carbon nuclear magnetic spectrum, respectively, of 1-phenyl-1-cyano-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline prepared in example 17 of the present invention;
FIG. 16 and FIG. 17 are a hydrogen nuclear magnetic spectrum and a carbon nuclear magnetic spectrum, respectively, of 1-phenyl-1-cyano-2-methyl-7-methoxy-1, 2,3, 4-tetrahydroisoquinoline prepared in example 18 of the present invention;
FIG. 18 and FIG. 19 are a hydrogen nuclear magnetic spectrum and a carbon nuclear magnetic spectrum, respectively, of 1-phenyl-1-cyano-2, 6, 7-trimethyl-1, 2,3, 4-tetrahydroisoquinoline prepared in example 19 of the present invention.
Detailed Description
Preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the description of the preferred embodiment is only for purposes of illustration and understanding, and is not intended to limit the invention.
Example 1A 1-phenyl-1-cyano-2-methyl-1, 2,3, 4-tetrahydroisoquinoline synthesis method
This example provides a synthesis method of 1-phenyl-1-cyano-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, which comprises weighing 103.7mg of 1-phenyl-3, 4-dihydroisoquinoline and 212.9mg of methyl iodide, adding into 3mL of 1, 2-dichloroethane, stirring continuously to dissolve, heating to 40 deg.C, reacting at 40 deg.C for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously at room temperature to perform addition reaction for 24h, detecting by TLC after the reaction is finished, extracting the reaction solution with dichloromethane, purifying by column chromatography to obtain 113.7mg of 1-phenyl-1-cyano-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, the nuclear magnetic patterns are shown in figure 1 and figure 2, the yield is 92 percent, and the chemical reaction formula is
2-Methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:White solid,98％yield.Rf＝0.55(petroleum ether/ethyl acetate 5:1).1H NMR(400MHz,CDCl3) δ 7.56(dd, J ═ 7.5,1.8Hz,2H), 7.43-7.27 (m,3H), 7.22-7.09 (m,2H), 7.07-6.94 (m,1H),6.74(d, J ═ 8.0Hz,1H), 3.39-3.23 (m,1H), 3.13-2.94 (m,2H),2.82(dd, J ═ 16.2,1.5Hz,1H),2.26(s,3H) (fig. 1).13C NMR(100MHz,CDCl3) δ 140.8,135.9,134.0,129.3,128.9,128.6,128.6,127.8,126.5,117.1,70.5,49.6,40.7,29.1 (fig. 2).
Example 2 ~ 111-phenyl-1-cyano-2-methyl-1, 2,3, 4-four hydrogen isoquinoline synthesis method
Examples 2 to 11 respectively provide a method for synthesizing 1-phenyl-1-cyano-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, which is substantially the same as example 1 except that the raw materials and some process parameters are different, and the specific data are shown in table 1.
Table 1: examples 2 to 11 provide methods for synthesizing 1-phenyl-1-cyano-2-methyl-1, 2,3, 4-tetrahydroisoquinoline, the parameter tables of which are set forth below
The other steps are the same as the example 1, and the obtained products are all 1-phenyl-1-cyano-2-methyl-1, 2,3, 4-tetrahydroisoquinoline with the structural formula
Example 12A 1-cyano-2-methyl-1- (3-tolyl) -1,2,3, 4-tetrahydroisoquinoline synthesis method
This example provides a method for synthesizing 1-cyano-2-methyl-1- (3-tolyl) -1,2,3, 4-tetrahydroisoquinoline, which comprises weighing 110.6mg of 1- (3-tolyl) -3, 4-dihydroisoquinoline and 212.9mg of iodomethane, adding into 3mL of 1, 2-dichloroethane, stirring and dissolving continuously, heating to 40 deg.C, reacting at 40 deg.C for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously and reacting for 48h at room temperature, detecting by TLC after the reaction is finished, extracting the reaction solution with dichloromethane, purifying by column chromatography to obtain 130.3mg of 1-cyano-2-methyl-1- (3-tolyl) -1,2,3, 4-tetrahydroisoquinoline with a yield of 99 percent and a chemical reaction formula of
2-Methyl-1-(m-tolyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:White solid,99％yield.Rf＝0.55(petroleumether/ethyl acetate 5:1).1H NMR(400MHz,CDCl3) δ 7.36(s,2H),7.25(s,1H), 7.21-7.09 (m,3H),7.03(t, J ═ 6.9Hz,1H),6.76(d, J ═ 7.9Hz,1H), 3.37-3.24 (m,1H), 3.14-2.95 (m,2H),2.82(d, J ═ 16.0Hz,1H),2.34(s,3H),2.26(s,3H) (fig. 3).13C NMR(100MHz,CDCl3)δ140.7,138.4,136.0,133.9,129.4,129.3,128.9,128.4,128.3,127.8,126.5,125.0,117.2,70.5,49.6,40.8,29.1,21.5 (fig. 4).
Example 13A 1-cyano-2-methyl-1- (4-tolyl) -1,2,3, 4-tetrahydroisoquinoline synthesis method
This example provides a method for synthesizing 1-cyano-2-methyl-1- (4-tolyl) -1,2,3, 4-tetrahydroisoquinoline, which comprises weighing 110.6mg of 1- (4-tolyl) -3, 4-dihydroisoquinoline and 212.9mg of iodomethane, adding into 3mL of 1, 2-dichloroethane, stirring and dissolving continuously, heating to 40 deg.C, reacting at 40 deg.C for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously and reacting for 48h at room temperature, detecting by TLC after the reaction is finished, extracting the reaction solution with dichloromethane, purifying by column chromatography to obtain 123.6mg of 1-cyano-2-methyl-1- (4-tolyl) -1,2,3, 4-tetrahydroisoquinoline with a yield of 94%, and the chemical reaction formula is
2-Methyl-1-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:White solid,94％yield.Rf＝0.56(petroleumether/ethyl acetate 5:1)1H NMR (400MHz, CDCl3) δ 7.43(d, J ═ 7.8Hz,2H),7.16(d, J ═ 8.5Hz,4H),7.03(t, J ═ 7.0Hz,1H),6.75(d, J ═ 7.9Hz,1H), 3.37-3.23 (m,1H), 3.14-2.95 (m,2H),2.81(d, J ═ 16.0Hz,1H),2.35(s,3H),2.26(s,3H) (fig. 5).13C NMR (100MHz, CDCl3) delta 138.5,137.9,136.1,134.0,129.3,128.9,127.8,127.7,126.5,117.3,70.3,49.6,40.7,29.1,21.1 (FIG. 6).
Example 14A 1-cyano-2-methyl-1- (4-chlorophenyl) -1,2,3, 4-tetrahydroisoquinoline synthesis method
This example provides a synthesis method of 1-cyano-2-methyl-1- (4-chlorophenyl) -1,2,3, 4-tetrahydroisoquinoline, which comprises weighing 120.9mg of 1- (4-chlorophenyl) -3, 4-dihydroisoquinoline and 212.9mg of iodomethane, adding into 3mL of 1, 2-dichloroethane, stirring continuously to dissolve, heating to 40 deg.C, reacting at 40 deg.C for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously at room temperature to carry out addition reaction for 48h, detecting by TLC after the reaction is finished, extracting the reaction solution with dichloromethane by column chromatography, purifying to obtain 132.5mg of 1-cyano-2-methyl-1- (4-chlorophenyl) -1,2,3, 4-tetrahydroisoquinoline with a yield of 94%, and the chemical reaction formula is
1-(4-Chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:White solid,94％yield.Rf＝0.56(petroleumether/ethyl acetate 5:1).1HNMR(400MHz,CDCl3) δ 7.51(d, J ═ 8.5Hz,2H),7.34(d, J ═ 8.7Hz,2H), 7.22-7.10 (m,2H),7.05(t, J ═ 7.4Hz,1H),6.71(d, J ═ 8.0Hz,1H), 3.36-3.22 (m,1H), 3.14-2.94 (m,2H),2.82(dd, J ═ 16.2,1.5Hz,1H),2.25(s,3H) (fig. 7).13C NMR(100MHz,CDCl3) δ 139.5,135.4,134.6,134.0,129.2,129.1,129.1,128.8,128.0,126.7,116.8,70.0,49.5,40.7,29.0 (fig. 8).
Example 15A 1-cyano-2-methyl-1- (4-fluorophenyl) -1,2,3, 4-tetrahydroisoquinoline synthesis method
This example provides a method for synthesizing 1-cyano-2-methyl-1- (4-fluorophenyl) -1,2,3, 4-tetrahydroisoquinoline, which comprises weighing 112.7mg of 1- (4-fluorophenyl) -3, 4-dihydroisoquinoline and 212.9mg of iodomethane, adding into 3mL of 1, 2-dichloroethane, stirring continuously to dissolve, heating to 40 deg.C, reacting at 40 deg.C for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously at room temperature to carry out addition reaction for 48h, detecting by TLC after the reaction is finished, extracting the reaction solution by using dichloromethane, purifying to obtain 116.6mg of 1-cyano-2-methyl-1- (4-fluorophenyl) -1,2,3, 4-tetrahydroisoquinoline with a yield of 88%, and the chemical reaction formula is
1-(4-Fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:Colorless liquid,88％yield.Rf＝0.54(petroleum ether/ethyl acetate 5:1).1H NMR(400MHz,CDCl3) δ 7.55(dd, J ═ 8.6,5.3Hz,2H), 7.24-7.12 (m,2H),7.05(t, J ═ 8.6Hz,3H),6.72(d, J ═ 7.9Hz,1H), 3.35-3.23 (m,1H), 3.13-2.95 (m,2H),2.82(dd, J ═ 16.2,1.4Hz,1H),2.25(s,3H) (fig. 9).13C NMR(100MHz,CDCl3) δ 163.71(d, J ═ 248.2Hz),161.48(s),136.71(d, J ═ 3.2Hz),135.64(s),133.96(s),129.60(d, J ═ 8.3Hz),129.09(d, J ═ 12.9Hz),127.96(s),126.61(s),116.99(s),115.64(s),115.42(s),69.89(s),49.56(s),40.65(s),29.00(s) (fig. 10).19F NMR(376MHz,CDCl3) Delta-113.1 (FIG. 11).
Example 16A 1-cyano-2-methyl-1- (4-methoxyphenyl) -1,2,3, 4-tetrahydroisoquinoline synthesis method
This example provides a method for synthesizing 1-cyano-2-methyl-1- (4-methoxyphenyl) -1,2,3, 4-tetrahydroisoquinoline, which comprises weighing 118.7mg of 1- (4-methoxyphenyl) -3, 4-dihydroisoquinoline and 212.9mg of iodomethane, respectively, adding into 3mL of 1, 2-dichloroethane, stirring and dissolving continuously, heating to 40 deg.C, maintaining 40 deg.C for reaction for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously at room temperature for addition reaction for 48h, detecting by TLC after the reaction is finished, extracting the reaction solution with dichloromethane, purifying by column chromatography to obtain 128.6mg of 1-cyano-2-methyl-1- (4-methoxyphenyl) -1,2,3, 4-tetrahydroisoquinoline with a yield of 92%, the chemical reaction formula is
1-(4-Methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:White solid,92％yield.Rf＝0.45(petroleumether/ethyl acetate 5:1).1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.7Hz,2H),7.22–7.10(m,2H),7.09–6.98(m,1H),6.88(d,J＝8.9Hz,2H),6.76(d,J＝7.9Hz,1H),3.81(s,3H),3.35–3.22(m,1H),3.13–2.95(m,2H),2.81(dd,J ═ 16.2,1.5Hz,1H),2.26(s,3H) (fig. 12).13C NMR(100MHz,CDCl3) δ 159.7,136.1,134.0,132.8,129.3,129.0,128.9,127.8,126.5,117.3,113.8,69.9,55.3,49.6,40.6,29.1 (fig. 13).
Example 17A 1-phenyl-1-cyano-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline synthesis method
This example provides a synthesis method of 1-phenyl-1-cyano-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline, which comprises weighing 110.6mg of 1-phenyl-7-methyl-3, 4-dihydroisoquinoline and 212.9mg of iodomethane, adding into 3mL of 1, 2-dichloroethane, stirring and dissolving continuously, heating to 40 deg.C, reacting at 40 deg.C for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously at room temperature for addition reaction for 48h, detecting by TLC after the reaction is finished, extracting the reaction solution with dichloromethane, purifying by column chromatography to obtain 125.0mg of 1-phenyl-1-cyano-2, 7-dimethyl-1, 2,3, 4-tetrahydroisoquinoline with a yield of 95% and a chemical reaction formula of
2,7-Dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:Colorless liquid,95％yield.Rf＝0.58(petroleumether/ethyl acetate 5:1).1H NMR(400MHz,CDCl3) δ 7.65-7.48 (m,2H),7.36(d, J ═ 6.0Hz,3H),7.01(dd, J ═ 22.2,7.8Hz,2H),6.53(s,1H), 3.32-3.19 (m,1H), 3.12-2.92 (m,2H),2.78(d, J ═ 15.8Hz,1H),2.25(s,3H),2.13(s,3H) (fig. 14).13C NMR(100MHz,CDCl3) δ 140.9,136.1,135.6,130.9,129.5,128.9,128.8,128.6,128.5,127.8,117.3,70.5,49.7,40.7,28.7,21.0 (fig. 15).
Example 18A synthetic method of 1-phenyl-1-cyano-2-methyl-7-methoxy-1, 2,3, 4-tetrahydroisoquinoline
This example provides a method for synthesizing 1-phenyl-1-cyano-2-methyl-7-methoxy-1, 2,3, 4-tetrahydroisoquinoline, which comprises weighing 118.7mg of 1-phenyl-7-methyl-3, 4-dihydroisoquinoline and 212.9mg of iodomethane, respectively, adding into 3mL of 1, 2-dichloroethane, stirring and dissolving continuously, heating to 40 deg.C, reacting for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously and reacting for 48h at room temperature, detecting by TLC, extracting the reaction solution with dichloromethane, purifying by column chromatography to obtain 120.0mg of 1-phenyl-1-cyano-2-methyl-7-methoxy-1, 2,3, 4-tetrahydroisoquinoline with a yield of 86%, and the chemical reaction formula is
7-Methoxy-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:Colorless liquid,86％yield.Rf＝0.50(petroleum ether/ethyl acetate 5:1).1H NMR(400MHz,CDCl3) δ 7.56(d, J ═ 6.2Hz,2H),7.36(d, J ═ 6.5Hz,3H),7.07(d, J ═ 8.4Hz,1H),6.76(dd, J ═ 8.4,1.9Hz,1H),6.24(d, J ═ 1.8Hz,1H),3.59(s,3H), 3.29-3.17 (m,1H), 3.12-2.93 (m,2H),2.76(d, J ═ 15.3Hz,1H),2.25(s,3H) (fig. 16).13C NMR(100MHz,CDCl3) δ 157.9,140.7,136.7,129.9,128.7,128.6,127.8,126.1,117.1,114.3,114.1,70.6,55.2,49.8,40.8,28.3 (fig. 17).
Example 19A 1-phenyl-1-cyano-2, 6, 7-trimethyl-1, 2,3, 4-tetrahydroisoquinoline synthesis method
This example provides a synthesis method of 1-phenyl-1-cyano-2, 6, 7-trimethyl-1, 2,3, 4-tetrahydroisoquinoline, which comprises weighing 117.7mg of 1-phenyl-6, 7-dimethyl-3, 4-dihydroisoquinoline and 212.9mg of methyl iodide, adding into 3mL of 1, 2-dichloroethane, stirring and dissolving continuously, heating to 40 deg.C, reacting for 30min, stirring continuously and cooling to room temperature, adding 99.2mg of trimethylsilyl cyanide, 58.1mg of potassium fluoride and 26.5mg of sodium carbonate, stirring continuously and reacting for 48h at room temperature, detecting by TLC after the reaction is finished, extracting the reaction solution with dichloromethane, purifying by column chromatography to obtain 128.6mg of 1-phenyl-1-cyano-2, 6, 7-trimethyl-1, 2,3, 4-tetrahydroisoquinoline with a yield of 93%, the chemical reaction formula is
2,6,7-Trimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile:White solid,93％yield.Rf＝0.50(petroleum ether/ethyl acetate 5:1).1H NMR(400MHz,CDCl3) δ 7.66-7.48 (m,2H), 7.46-7.28 (m,3H),6.92(s,1H),6.48(s,1H), 3.30-3.16 (m,1H),3.02(ddd, J ═ 15.3,11.9,4.3Hz,2H),2.74(d, J ═ 15.7Hz,1H),2.24(s,3H),2.18(s,3H),2.03(s,3H) (fig. 18).13C NMR(101MHz,CDCl3) δ 141.0,136.6,135.0,133.2,131.2,129.9,128.5,127.8,117.4,70.3,49.8,40.7,28.6,19.4,19.4 (fig. 19).
Although the present invention has been described in detail with reference to the above embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described above, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A synthetic method of alpha-cyano quaternary carbon substituted tetrahydroisoquinoline comprises the steps of adding isoquinoline compounds into an organic solvent, adding methyl iodide, heating, carrying out salification activation, cooling to room temperature, adding a cyano source, a fluorine reagent and a base, carrying out addition reaction, and obtaining the alpha-cyano quaternary carbon substituted tetrahydroisoquinoline,
the chemical reaction formula is as follows:
wherein R is an alkyl group with any one of 1-6 carbon atoms;
R1and R2Are respectively-H and-CH3or-OCH3;
RXis-F, -Cl, -CH3and-OCH3One of (1);
the organic solvent is dichloromethane, 1, 2-dichloroethane, dioxane, toluene or methanol;
the cyano source is trimethyl cyano silane;
the fluorine reagent is sodium fluoride or potassium fluoride;
the alkali is sodium carbonate, lithium carbonate, potassium phosphate or triethylamine.
2. The method for synthesizing an alpha-cyano quaternary carbon-substituted tetrahydroisoquinoline of claim 1, wherein the method comprises: the molar ratio of the cyano source to the isoquinoline compound is 1-2: 1.
3. The method for synthesizing an alpha-cyano quaternary carbon-substituted tetrahydroisoquinoline of claim 1, wherein the method comprises: the molar ratio of the fluorine reagent to the isoquinoline compounds is 1-2: 1.
4. the method for synthesizing an alpha-cyano quaternary carbon-substituted tetrahydroisoquinoline of claim 1, wherein the method comprises: the molar ratio of the alkali to the isoquinoline compound is 0.34-1: 1.
5. The method for synthesizing an alpha-cyano quaternary carbon-substituted tetrahydroisoquinoline of claim 1, wherein the method comprises: the heating reaction is carried out at the temperature of 30-80 ℃ for 30-60 min.
6. The method for synthesizing an alpha-cyano quaternary carbon-substituted tetrahydroisoquinoline of claim 1, wherein the method comprises: the time of the addition reaction is 24-48 h.
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