CN111978322A - Synthesis method of tetrahydroisoquinolino ring compound and tetrahydro-beta-carbolino ring compound - Google Patents

Synthesis method of tetrahydroisoquinolino ring compound and tetrahydro-beta-carbolino ring compound Download PDF

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CN111978322A
CN111978322A CN202011010566.4A CN202011010566A CN111978322A CN 111978322 A CN111978322 A CN 111978322A CN 202011010566 A CN202011010566 A CN 202011010566A CN 111978322 A CN111978322 A CN 111978322A
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CN111978322B (en
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宋巧
王周玉
钱珊
刘艳
杨光余
蔡林林
纪光露
何展军
王杰
王悦二
冯金凤
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Research Institute Of Xihua University Yibin
Xihua University
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Xihua University
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract

The invention provides a synthesis method of a tetrahydroisoquinolino ring compound and a tetrahydro-beta-carbolino ring compound, belonging to the technical field of synthesis. The method for synthesizing the tetrahydroisoquinoline and tetrahydro-beta-carboline ring compound, provided by the invention, has the advantages of easiness in obtaining raw materials, simple steps, high synthesis efficiency, mild reaction conditions, environmental friendliness and strong universality by taking the halogenated amide as the raw material after synthesizing the halogenated amide with a specific structure and carrying out one-pot series reaction of intramolecular ring closure reaction and reduction reaction.

Description

Synthesis method of tetrahydroisoquinolino ring compound and tetrahydro-beta-carbolino ring compound
Technical Field
The invention belongs to the technical field of synthesis, and particularly relates to a synthetic method of tetrahydroisoquinoline fused ring and tetrahydro-beta-carboline fused ring compounds.
Background
The tetrahydroisoquinolino ring backbone and the tetrahydro- β -carbolino ring backbone are two very important classes of aza ring structures. According to statistics, the tetrahydroisoquinoline ring skeleton and the tetrahydro-beta-carboline ring skeleton as key structural units exist in more than 26000 natural products and drug molecules with important physiological activities. For example, tetrahydroisoquinoline and cyclic alkaloid Tetrahydropalmatine extracted from corydalis plants not only has good analgesic activity, but also is expected to be used for treating heart diseases and liver injury; the beta-carboline alkaloid Harmicine extracted from Malaysia pistia plants has strong leishmania resisting activity; valbenazine, a novel vesicular monoamine transporter 2(VMAT2) inhibitor, was approved by the FDA for the treatment of chorea in 2017. In addition, Valbenazine is being investigated for the treatment of tardive dyskinesia.
Because the tetrahydroisoquinolino ring compounds and the tetrahydro-beta-carbolino ring compounds have complex structures, wide biological activity and huge application value, the yield of the compounds containing related frameworks extracted from natural products is low and the difficulty is high. Therefore, the development of a new green, economic and efficient synthetic method for constructing the tetrahydroisoquinoline fused ring derivative and the tetrahydro-beta-carboline fused ring derivative has important scientific significance and practical value. Therefore, researchers at home and abroad have conducted more exploration on methods for constructing tetrahydroisoquinoline fused ring frameworks and tetrahydro-beta-carboline fused ring frameworks, but the existing methods often have one or more of the following problems:
(1) the synthesis steps are long, resulting in low synthesis efficiency.
(2) The starting materials are difficult to obtain, and the application difficulty is increased.
(3) The reaction conditions are severe, so that the tolerance of the functional group is poor and the universality is not strong.
(4) The use of noble metal catalysts is costly and the heavy metal residues in the product are difficult to remove.
(5) The method uses flammable and explosive or highly toxic hazardous reagents, has potential safety hazards and is not environment-friendly.
For example, the document "Selvakumar J, Rao R S, Srinivaspriyan V, et al.Synthesis of Condensed tetrahydroquinoline Class of Alkaloids by using extrusion TfOH-media Imide Carbonylactivation. European Journal of Organic Chemistry,2015 (10): 2175. sup. 2188" discloses a route for synthesizing Tetrahydroisoquinoline and cyclic compounds by first performing a Bischler-Napieralski reaction using a TfOH-activated Imide and then performing a NaBH-NaBH4Reducing the formed imine to obtain a tetrahydroisoquinoline structure, separating to obtain an intermediate, and further using LiAlH4Reducing the remaining amide carbonyl group to construct the tetrahydroisoquinolino ring derivative. The method uses TfOH with stronger corrosivity, and has longer steps and lower yield.
Therefore, the method for preparing the tetrahydroisoquinolino-cyclic compound and the tetrahydro-beta-carbolino-cyclic compound, which has the advantages of easily obtained raw materials, simple steps, high synthesis efficiency, mild reaction conditions, environmental friendliness and strong universality, has great significance.
Disclosure of Invention
The invention aims to provide a method for preparing a tetrahydroisoquinolino ring compound or a tetrahydro-beta-carbolino ring compound, which has the advantages of easily obtained raw materials, simple steps, high synthesis efficiency, mild reaction conditions, environmental friendliness and strong universality.
The invention provides a synthesis method of a tetrahydroisoquinoline ring compound, which is characterized by comprising the following steps:
(1) and reacting the primary amine shown in the formula I with acyl halide shown in the formula II under the action of alkali to obtain the compound shown in the formula III.
(2) The halogenated amide shown in the formula III is subjected to amide and aromatic ring dehydration cyclization reaction under the action of an activating agent to obtain a compound shown in the formula IV;
(3) adding a reducing agent into the compound shown in the formula IV to react to obtain a tetrahydroisoquinoline ring-fused compound shown in the formula V;
the reaction route is as follows:
Figure BDA0002697425330000021
wherein n is an integer from 1 to 4; x is halogen; r1And R3Are respectively and independently selected from hydrogen and C1-3An alkoxy group; r2Selected from hydrogen, halogen, C1-3Alkyl, methoxy, t-butyldimethylsilyloxy, acetoxy; or R1And R2Linked to form a 3-5 membered saturated oxacyclyl group; r4、R5Each independently selected from hydrogen, phenyl, or R4And R5Are linked to form a phenyl group.
Further, R2Preferably hydrogen, halogen, C1-3Alkyl, t-butyldimethylsiloxy, acetoxy; r4、R5Preferably hydrogen; r1、R2And/or R3Is C1-3When alkoxy, methoxy is preferred; r1And R2Connection ofWhen a 3-to 5-membered saturated oxygen heterocycle group is formed, the oxygen heterocycle group is preferably a 5-membered one having 2 oxygen atoms, more preferably a 3-to 5-membered saturated oxygen heterocycle group
Figure BDA0002697425330000031
Further, when R in formula III2When the tert-butyldimethylsiloxy group is obtained, adding ethyl acetate saturated hydrogen chloride solution to react at room temperature to remove the tert-butyldimethylsiloxy group to obtain
Figure BDA0002697425330000032
Wherein n is an integer from 1 to 4, R1And R3Are respectively and independently selected from hydrogen and C1-3An alkoxy group; r2Selected from hydrogen, halogen, C1-3Alkyl, methoxy, tert-butyldimethylsilyloxy, acetoxy, R4、R5Each independently selected from hydrogen, phenyl, or R4And R5Are linked to form a phenyl group. .
The invention also provides a synthesis method of the tetrahydro-beta-carboline ring compound, which is characterized by comprising the following steps:
1) and reacting the primary amine shown in the formula VI with acyl halide shown in the formula VII under the action of alkali to obtain the compound shown in the formula VIII.
2) The halogenated amide shown in the formula VIII is subjected to amide and aromatic ring dehydration cyclization reaction under the action of an activating agent to obtain a compound shown in the formula IX,
3) adding a reducing agent into the compound shown in the formula IX to react to obtain the tetrahydro-beta-carboline ring-fused compound shown in the formula X, wherein the reaction route is as follows:
Figure BDA0002697425330000033
wherein n is an integer from 1 to 4, and X is halogen; r6Selected from alkyl, benzyl, trifluoromethanesulfonyl; .
Further, when R in formula XII6When the compound is trifluoromethanesulfonyl, sodium hydroxide can be further added, and trifluoromethanesulfonyl can be removed through methanol reflux reaction to obtain trifluoromethanesulfonyl
Figure BDA0002697425330000034
n is an integer from 1 to 4.
Further, in the step (1) and/or the step 1), the base is selected from at least one of organic base and inorganic base, preferably at least one of triethylamine, pyridine, 2-fluoropyridine, 2-chloropyridine, 2-iodopyridine, 4-dimethylaminopyridine, sodium hydroxide, sodium carbonate and sodium bicarbonate, and more preferably triethylamine; in the step (2) and/or the step 2), the activating agent is trifluoromethanesulfonic anhydride and pyridine base; the reducing agent in the step (3) and/or the step 3) is KBH4、NaBH3CN、NaBH(OAc)3、NaBH4Is preferably NaBH4。
Further, the pyridine base is selected from 2-chloropyridine, 2-iodopyridine and pyridine, preferably 2-fluoropyridine.
Further, the reaction conditions for dehydrating and cyclizing the amide and the aromatic ring in the step (2) and/or the step 2) of the above synthesis method are as follows: under the protection of argon, reacting at-90 to-60 ℃ for 25 to 35 minutes, heating to 30 to 50 ℃ and reacting for 1.5 to 2.5 hours or reacting at 110 to 130 ℃ for 15 to 20 minutes; the step (3) and/or the step 3) further comprises the following separation and purification steps: adding saturated sodium bicarbonate solution; extracting with dichloromethane, and mixing organic phases; drying with anhydrous sodium sulfate; filtering, concentrating, and purifying the residue by silica gel column chromatography.
Further, the reaction conditions for dehydrating and cyclizing the amide with the aromatic ring are as follows: reacting at-78 deg.C for 30min under the protection of argon, heating to 40 deg.C, and reacting for 2 hr or at 120 deg.C for 18 min.
Further, the reaction conditions in step (3) and/or step 3) of the synthesis method are room temperature reaction for 1.5-2.5 hours, preferably room temperature reaction for 2 hours.
Experimental results show that the method can successfully prepare the tetrahydroisoquinoline ring compound and the tetrahydro-beta-carboline ring compound, and has the advantages of simple operation, high yield, mild reaction conditions, environmental friendliness, strong universality and excellent industrial application prospect.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"base" refers to basic substances, including organic and inorganic bases.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
Halogen is fluorine, chlorine, bromine or iodine.
"alkyl" is a hydrocarbon radical derived from an alkane molecule by the removal of one hydrogen atom, e.g. methyl-CH3ethyl-CH3CH2And the like. C1～3Alkyl refers to a straight or branched hydrocarbon chain containing one to three carbon atoms.
T-butyldimethylsiloxy is represented by TBSO, acetoxy is represented by AcO, and trifluoromethanesulfonyl is represented by Tf.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a synthetic route for a chloroamide starting material.
FIG. 2 shows the general formula 1 of the synthetic route.
FIG. 3 shows general scheme 2.
Detailed Description
The raw material chloroamide used in the invention is synthesized by itself, the synthesis flow chart is shown in figure 1, and the synthesis method is as follows: the primary amine (1.0equiv.) and triethylamine (2.0equiv.) were dissolved in dichloromethane (1 mL per 0.1mol primary amine), cooled to 0 ℃, and the acid chloride (1.2equiv.) was added dropwise. After dropping, the system was warmed to room temperature and stirred for 1 h. Saturated aqueous sodium bicarbonate (1 mL per 0.1mol primary amine) was added. The organic phase was separated and the aqueous phase was extracted 2 times with dichloromethane (1 mL per 0.1mol of primary amine). The organic phases were combined and dried over anhydrous sodium sulfate for 10-20 h. Filtering, concentrating, and purifying the residue by silica gel column chromatography to obtain the corresponding amide.
The solvents used in the present invention are all available from Kyoto Chemicals, Inc. CH (CH)2Cl2With CaCl2After treatment, redistilled and added
Figure BDA0002697425330000051
Sealing and storing the molecular sieve; trifluoromethanesulfonic anhydride (Tf)2O) from Anyiji Chemicals, Inc., and with P2O5Steaming again after treatment, and storing in a sealed manner for no more than seven days; 2-fluoropyridine (2-F-Py) is purchased from Annaiji chemical reagent limited company column chromatography silica gel, and merck 300-400 mesh silica gel is adopted; a microwave reactor: anton Paar Multiwave Pro type. Nuclear magnetic resonance apparatus: bruker 400MHz type. High resolution mass spectrometer: SCIEX X500R QTOF type. Melting point apparatus: SGW X-4 type.
Examples 1,
1. The synthesis steps are as follows: primary amines
Figure BDA0002697425330000061
(1.0equiv.) and triethylamine (2.0equiv.) were dissolved in dichloromethane (1 mL per 0.1mol of primary amine), cooled to 0 deg.C, and the acid chloride was added dropwise
Figure BDA0002697425330000062
(1.2 equiv.). After dropping, the system was warmed to room temperature and stirred for 1 h. Saturated aqueous sodium bicarbonate (1 mL per 0.1mol primary amine) was added. The organic phase was separated and the aqueous phase was extracted 2 times with dichloromethane (1 mL per 0.1mol of primary amine). The organic phases were combined and dried over anhydrous sodium sulfate for 10-20 h. Filtering, concentrating, purifying the residue with silica gel column chromatography to obtain corresponding chloramide
Figure BDA0002697425330000063
Chloroamides
Figure BDA0002697425330000064
(0.5mmol,1.0equiv.) was dissolved in 10mL of anhydrous dichloromethane, and 2-F-Py (0.6mmol,1.2equiv.) was added under argon. After cooling the reaction system to-78 ℃, Tf was slowly added dropwise through a syringe2O (0.55mmol,1.1 equiv.). After dropping, the mixture was stirred at-78 ℃ for 30 min. The reaction system was warmed to 40 ℃ and stirred for 2 h. Cooling to room temperature, adding NaBH4(1mmol,2equiv.) and dry methanol (5mL), stirring was continued for 2 h. 10mL of saturated sodium bicarbonate solution was added, followed by extraction with dichloromethane (3X 8 mL). The organic phases were combined and dried over anhydrous sodium sulfate for 10-20 h. Filtering, concentrating, and purifying the residue by silica gel column chromatography. The general formula of the synthetic route is shown in figure 2.
2. The experimental results are as follows:
Figure BDA0002697425330000065
the yield was calculated as (product mass × raw material molecular weight)/(product molecular weight × raw material mass) × 100%, as follows.
The yield is 90 percent, and the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):7.00(d,J＝8.3Hz,1H),6.76–6.68(m,2H),3.77(s,3H),3.16–3.03(m,2H),3.03–2.89(m,2H),2.64(dd,J＝16.0,3.4Hz,1H),2.49(td,J＝11.7,4.0Hz,1H),2.34–2.23(m,2H),1.97–1.89(m,1H),1.73–1.61(m,2H),1.52–1.38(m,2H)；13C NMR(101MHz,CDCl3):157.69,139.55,129.71,126.79,111.71,110.36,63.67,57.00,55.26,52.99,31.34,28.70,25.46,25.14；HRMS(ESI):calcd for C14H20NO+(M+H)+:218.1539,found 218.1534.
example 2
1. The synthetic procedure is the same as example 1, and the general formula of the synthetic route is shown in figure 2, wherein, primary amine is
Figure BDA0002697425330000071
Acyl chloride is
Figure BDA0002697425330000072
The chloroamides are
Figure BDA0002697425330000073
2. The experimental results are as follows:
Figure BDA0002697425330000074
the yield is 88%; the purity is more than 90 percent; a colorless oil;1H NMR(400MHz,CDCl3):7.03(d,J＝8.4Hz,1H),6.71(dd,J＝8.4,2.6Hz,1H),6.62(d,J＝2.4Hz,1H),3.78(s,3H),3.45(t,J＝8.2Hz,1H),3.24–3.13(m,1H),3.13–2.97(m,2H),2.81–2.72(m,1H),2.68–2.51(m,2H),2.39–2.29(m,1H),1.97–1.83(m,2H),1.80–1.69(m,1H)；HRMS(ESI):calcd for C13H18NO+(M+H)+:204.1383,found 204.1379.
example 3
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000075
Acyl chloride is
Figure BDA0002697425330000076
The chloroamides are
Figure BDA0002697425330000077
2. The experimental results are as follows:
Figure BDA0002697425330000078
the yield is 78 percent; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):7.03–6.94(m,2H),6.89(s,1H),3.65–3.59(m,1H),3.18(m,1H),3.11–3.06(m,1H),3.05–2.98(m,1H),2.83–2.69(m,3H),2.43–2.35(m,1H),2.30(s,3H),1.99–1.88(m,2H),1.81–1.73(m,1H)；13C NMR(101MHz,CDCl3):137.63,135.55,130.58,128.35,127.14,126.32,63.17,53.47,48.39,30.58,27.71,22.28,21.12；HRMS(ESI):calcd for C13H18N+(M+H)+:188.1434,found 188.1444.
example 4
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000081
Acyl chloride is
Figure BDA0002697425330000082
The chloroamides are
Figure BDA0002697425330000083
2. The experimental results are as follows:
Figure BDA0002697425330000084
the yield is 73%; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):7.02(s,1H),7.00–6.93(m,2H),3.20–3.05(m,2H),3.03–2.89(m,2H),2.66(dd,J＝15.9,2.9Hz,1H),2.50(m,1H),2.38–2.31(m,2H),2.31(s,3H),1.96–1.89(m,1H),1.79–1.64(m,2H),1.56–1.37(m,2H)；13C NMR(101MHz,CDCl3):138.20,134.98,131.48,128.78,126.83,125.37,63.64,57.02,52.86,31.37,29.17,25.51,25.20,21.32；HRMS(ESI):calcd for C14H20N+(M+H)+:202.1590,found 202.1592.
example 5
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000085
Acyl chloride is
Figure BDA0002697425330000086
The chloroamides are
Figure BDA0002697425330000087
2. The experimental results are as follows:
Figure BDA0002697425330000088
the yield is 85 percent; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,CDCl3):7.19–7.02(m,4H),3.49–3.40(m,1H),3.20(m,1H),3.16–3.05(m,2H),2.89–2.79(m,1H),2.70–2.61(m,1H),2.54(dd,J＝17.0,8.8Hz,1H),2.41–2.31(m,1H),2.02–1.81(m,2H),1.81–1.69(m,1H)；HRMS(ESI):calcd for C12H16N+(M+H)+:174.1277,found 174.1270.
example 6
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000091
Acyl chloride is
Figure BDA0002697425330000092
The chloroamides are
Figure BDA0002697425330000093
2. The experimental results are as follows:
Figure BDA0002697425330000094
the yield is 81%; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,CDCl3):7.23–7.18(m,1H),7.18–7.10(m,2H),7.10–7.06(m,1H),3.25–3.09(m,2H),3.03–2.91(m,2H),2.71(dd,J＝16.4,3.4Hz,1H),2.53(m 1H),2.36–2.27(m,2H),1.97–1.89(m,1H),1.75–1.65(m,2H),1.53–1.37(m,2H)；HRMS(ESI):calcd for C12H16N+(M+H)+:188.1434,found 188.1424.
example 7
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000095
Acyl chloride is
Figure BDA0002697425330000096
The chloroamides are
Figure BDA0002697425330000097
2. The experimental results are as follows:
Figure BDA0002697425330000098
the yield is 84%; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):6.68(s,1H),6.53(s,1H),5.89–5.87(m,2H),3.13–3.03(m,1H),3.03–2.94(m,2H),2.94–2.88(m,1H),2.58(dd,J＝16.1,3.9Hz,1H),2.47(m,1H),2.33–2.24(m,1H),2.22–2.16(m,1H),1.94–1.87(m,1H),1.72–1.62(m,2H),1.53–1.36(m,2H)；13C NMR(101MHz,CDCl3)145.87,145.69,131.60,127.80,108.46,105.01,100.64,63.51,56.87,52.83,31.62,29.60,25.45,25.09.HRMS(ESI):calcd for C14H18NO2 +(M+H)+:232.1332,found 232.1321.
example 8
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000101
Acyl chloride is
Figure BDA0002697425330000102
The chloroamides are
Figure BDA0002697425330000103
2. The experimental results are as follows:
Figure BDA0002697425330000104
the yield is 79 percent; the purity is more than 90 percent; a colorless oil;1H NMR(400MHz,CDCl3):7.03(d,J＝8.4Hz,1H),6.71(dd,J＝8.4,2.6Hz,1H),6.62(d,J＝2.4Hz,1H),3.78(s,3H),3.45(t,J＝8.2Hz,1H),3.24–3.13(m,1H),3.13–2.97(m,2H),2.81–2.72(m,1H),2.68–2.51(m,2H),2.39–2.29(m,1H),1.97–1.83(m,2H),1.80–1.69(m,1H)；HRMS(ESI):calcd for C13H18NO+(M+H)+:204.1383,found 204.1377.
example 9
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000105
Acyl chloride is
Figure BDA0002697425330000106
The chloroamides are
Figure BDA0002697425330000107
2. The experimental results are as follows:
Figure BDA0002697425330000108
the yield is 83 percent; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):7.00(d,J＝8.3Hz,1H),6.76–6.68(m,2H),3.77(s,3H),3.16–3.03(m,2H),3.03–2.89(m,2H),2.64(dd,J＝16.0,3.4Hz,1H),2.49(m,1H),2.34–2.23(m,2H),1.97–1.89(m,1H),1.73–1.61(m,2H),1.52–1.38(m,2H)；HRMS(ESI):calcd for C14H20NO+(M+H)+:218.1539,found 218.1536.
example 10
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000111
Acyl chloride is
Figure BDA0002697425330000112
The chloroamides are
Figure BDA0002697425330000113
2. The experimental results are as follows:
Figure BDA0002697425330000114
the yield is 68 percent; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):7.11–7.05(m,1H),6.91(d,J＝1.9Hz,1H),6.86(dd,J＝8.2,2.3Hz,1H),3.20–3.09(m,2H),3.04–2.93(m,2H),2.74–2.65(m,1H),2.59–2.47(m,1H),2.36–2.30(m,1H),2.28(s,3H),2.26–2.20(m,1H),1.96–1.86(m,1H),1.75–1.64(m,2H),1.51–1.43(m,2H)；13C NMR(101MHz,CDCl3):169.76,148.72,139.66,132.16,129.76,119.27,117.82,63.34,56.81,52.62,31.14,29.71,28.92,25.35,21.14；HRMS(ESI):calcd for C15H20NO2 +(M+H)+:246.1489,found 246.1493.
example 11
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000115
Acyl chloride is
Figure BDA0002697425330000116
The chloroamides are
Figure BDA0002697425330000117
2. The experimental results are as follows:
Figure BDA0002697425330000121
the yield is 75%; the purity is more than 90 percent; pale yellow oil1H NMR(400MHz,CDCl3):6.92(d,J＝8.2Hz,1H),6.67(d,J＝2.3Hz,1H),6.62(dd,J＝8.2,2.4Hz,1H),3.16–3.03(m,2H),3.01–2.88(m,2H),2.63(dd,J＝15.9,3.3Hz,1H),2.50(td,J＝11.7,4.1Hz,1H),2.35–2.17(m,2H),1.97–1.86(m,1H),1.76–1.63(m,2H),1.54–1.40(m,2H),0.97(s,9H),0.17(d,J＝1.0Hz,6H)；13C NMR(101MHz,CDCl3):153.52,139.39,129.57,127.22,117.98,116.25,63.44,56.95,52.98,31.20,29.71,28.70,25.76,25.43,25.09,18.23；HRMS(ESI):calcd for C19H32NOSi+(M+H)+:318.2248,found 318.2239.
Example 12
1. The synthesis steps are as follows: the product obtained in example 11 (60mg, 0.19mmol) was dissolved in 4mL of a saturated hydrogen chloride solution of ethyl acetate, and stirred at room temperature for 10min to precipitate a white solid. And filtering the solid, washing with ethyl acetate, and drying in vacuum to obtain the product.
2. The experimental results are as follows:
Figure BDA0002697425330000122
the yield is 80%; the purity is more than 90 percent; melting point: 183 ℃ and 184 ℃.1H NMR(400MHz,DMSO-d6):9.59(s,1H),7.00(d,J＝8.7Hz,1H),6.73(s,2H),4.32(s,1H),3.45(d,J＝11.3Hz,2H),3.38–3.22(m,3H),3.11(s,1H),2.78(d,J＝15.4Hz,1H),2.11–1.86(m,2H),1.83–1.53(m,3H)；13C NMR(101MHz,DMSO-d6):156.68,133.82,130.19,122.23,115.64,111.66,63.17,55.13,51.58,28.43,25.19,22.95,22.56；HRMS(ESI):calcd for C13H18NO+(M+H)+:204.1383,found 204.1381.
Example 13
1. The synthesis steps are as follows: primary amines
Figure BDA0002697425330000123
(1.0equiv.) and triethylamine (2.0equiv.) were dissolved in dichloromethane (1 mL per 0.1mol of primary amine), cooled to 0 deg.C, and the acid chloride was added dropwise
Figure BDA0002697425330000124
(1.2 equiv.). After dropping, the system was warmed to room temperature and stirred for 1 h. Saturated aqueous sodium bicarbonate (1 mL per 0.1mol primary amine) was added. The organic phase was separated and the aqueous phase was extracted 2 times with dichloromethane (1 mL per 0.1mol of primary amine). The organic phases were combined and dried over anhydrous sodium sulfate for 10-20 h. Filtering, concentrating, purifying the residue with silica gel column chromatography to obtain corresponding chloramide
Figure BDA0002697425330000131
Chloroamides
Figure BDA0002697425330000132
(0.5mmol,1.0equiv.) was dissolved in 10mL of anhydrous dichloromethane, and 2-F-Py (0.6mmol,1.2equiv.) was added under argon. After cooling the reaction system to-78 ℃, Tf was slowly added dropwise through a syringe2O (0.55mmol,1.1 equiv.). After dropping, the mixture was stirred at-78 ℃ for 30 min. The reaction solution was transferred to a glass sealed tube and heated to 120 ℃ with microwave for 18 min. Cooling to room temperature, adding NaBH4(1mmol,2equiv.) and dry methanol (5mL), stirring was continued for 2 h. 10mL of saturated sodium bicarbonate solution was added, followed by extraction with dichloromethane (3X 8 mL). The organic phases were combined and dried over anhydrous sodium sulfate for 10-20 h. Filtering, concentrating, and purifying the residue with silica gel column chromatography to obtain the final product, wherein the general formula of the synthetic route is shown in FIG. 3.
2. The experimental results are as follows:
Figure BDA0002697425330000133
the yield is 59 percent; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,DMSO-d6):7.55(s,1H),7.47(d,J＝8.1Hz,1H),7.24(d,J＝8.2Hz,1H),4.84–4.58(m,1H),3.72–3.55(m,1H),3.52–3.38(m,1H),3.32–3.20(m,2H),3.17–2.85(m,2H),2.74–2.56(m,1H),2.15–1.83(m,3H)；13C NMR(101MHz,DMSO-d6):135.35,132.26,131.72,131.62,130.69,121.98,63.26,55.81,47.96,32.84,26.35,22.98；HRMS(ESI):calcd for C12H15BrN+(M+H)+:252.0382,found 252.0374.
example 14
1. The synthesis steps are as follows: in the same manner as example 13, the general formula of the synthetic route is shown in FIG. 3, wherein primary amine is
Figure BDA0002697425330000134
Acyl chloride is
Figure BDA0002697425330000135
The chloroamides are
Figure BDA0002697425330000141
2. The experimental results are as follows:
Figure BDA0002697425330000142
the yield is 68 percent; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,DMSO-d6):7.61–7.44(m,2H),7.21(d,J＝8.2Hz,1H),4.45(d,J＝38.9Hz,1H),3.61–3.36(m,4H),3.22–2.85(m,2H),2.68(d,J＝13.0Hz,1H),1.95(dd,J＝21.2,10.4Hz,2H),1.84(d,J＝13.4Hz,1H),1.76–1.62(m,2H)；13C NMR(101MHz,DMSO-d6)135.61,131.98,131.44,131.03,128.26,120.28,62.73,55.11,50.89,28.27,25.61,22.86,22.60；HRMS(ESI):calcd for C13H17BrN+(M+H)+:266.0539,found 266.0536.
example 15
1. The synthesis steps are as follows: in the same manner as example 13, the general formula of the synthetic route is shown in FIG. 3, wherein primary amine is
Figure BDA0002697425330000143
Acyl chloride is
Figure BDA0002697425330000144
The chloroamides are
Figure BDA0002697425330000145
2. The experimental results are as follows:
Figure BDA0002697425330000146
the yield is 62 percent; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,CDCl3):7.21(dd,J＝8.2,1.9Hz,1H),7.17–7.07(m,2H),4.94–4.75(m,1H),4.05–3.83(m,1H),3.66–3.49(m,1H),3.35–3.19(m,1H),3.17–2.99(m,2H),2.90(d,J＝16.6Hz,1H),2.78–2.66(m,1H),2.26–2.16(m,1H),2.12–1.97(m,2H)；13C NMR(101MHz,CDCl3):133.62,133.53,129.96,129.92,128.25,126.46,60.53,53.82,46.97,32.58,24.93,22.87；HRMS(ESI):calcd for C12H15ClN+(M+H)+:208.0888,found 208.0891.
example 16
1. The synthesis steps are as follows: in the same manner as example 13, the general formula of the synthetic route is shown in FIG. 3, wherein primary amine is
Figure BDA0002697425330000151
Acyl chloride is
Figure BDA0002697425330000152
The chloroamides are
Figure BDA0002697425330000153
2. The experimental results are as follows:
Figure BDA0002697425330000154
the yield is 71%; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,DMSO-d6):7.46(s,1H),7.37(dt,J＝11.3,8.9Hz,1H),7.27(d,J＝8.3Hz,1H),4.43(dd,J＝29.3,19.6Hz,1H),3.59–3.35(m,3H),3.27(dd,J＝25.0,7.5Hz,1H),3.14(dt,J＝22.0,10.9Hz,1H),3.05–2.86(m,1H),2.67(d,J＝12.4Hz,1H),2.10–1.98(m,1H),1.95(dd,J＝16.7,8.7Hz,1H),1.86–1.62(m,3H)；13C NMR(101MHz,CD3OD):135.62,134.44,132.10,131.43,129.82,126.64,65.15,57.08,53.08,29.96,26.73,23.67,22.61.HRMS(ESI):calcd for C13H17ClN+(M+H)+:222.1044,found 222.1036.
example 17
1. The synthesis steps are as follows: in the same manner as example 13, the general formula of the synthetic route is shown in FIG. 3, wherein primary amine is
Figure BDA0002697425330000155
Acyl chloride is
Figure BDA0002697425330000156
The chloroamides are
Figure BDA0002697425330000157
2. The experimental results are as follows:
Figure BDA0002697425330000158
the yield is 66%; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,CDCl3):7.08–7.01(m,1H),6.86–6.72(m,2H),3.43–3.36(m,1H),3.22–3.16(m,1H),3.12–2.99(m,2H),2.83–2.74(m,1H),2.68–2.58(m,1H),2.57–2.48(m,1H),2.37–2.27(m,1H),2.01–1.79(m,2H),1.77–1.65(m,1H)；13C NMR(101MHz,CDCl3):162.30,159.88,140.79(d,J＝7.0Hz),129.80(d,J＝7.9Hz),113.01(d,J＝21.2Hz),112.20(d,J＝21.2Hz),63.35(d,J＝1.9Hz),53.26,48.39,30.11,27.88,22.13；HRMS(ESI):calcd for C12H15FN+(M+H)+:192.1183,found 192.1175.
example 18
1. The synthesis steps are as follows: in the same manner as example 13, the general formula of the synthetic route is shown in FIG. 3, wherein primary amine is
Figure BDA0002697425330000161
Acyl chloride is
Figure BDA0002697425330000162
The chloroamides are
Figure BDA0002697425330000163
2. The experimental results are as follows:
Figure BDA0002697425330000164
the yield is 73%; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):7.02(t,J＝7.1Hz,1H),6.89(d,J＝10.7Hz,1H),6.85–6.76(m,1H),3.19–3.04(m,2H),3.02–2.90(m,2H),2.66(d,J＝15.4Hz,1H),2.53–2.44(m,1H),2.35–2.19(m,2H),1.97–1.88(m,1H),1.75–1.63(m,2H),1.55–1.39(m,2H),13C NMR(101MHz,CDCl3):162.45,160.04,140.40(d,J＝6.6Hz),130.12(d,J＝7.9Hz),113.02(d,J＝21.3Hz),111.44(d,J＝22.0Hz),63.36,56.86,52.78,31.23,28.80,25.40,25.01；HRMS(ESI):calcd for C13H17FN+(M+H)+:206.1340,found 206.1338.
example 19
1. The synthesis steps are as follows: in the same manner as example 13, the general formula of the synthetic route is shown in FIG. 3, wherein primary amine is
Figure BDA0002697425330000165
Acyl chloride is
Figure BDA0002697425330000166
The chloroamides are
Figure BDA0002697425330000167
2. The experimental results are as follows:
Figure BDA0002697425330000168
the yield is 88%; the purity is more than 90 percent; a colorless oil;1H NMR(400MHz,CD3OD):7.32(t,J＝8.0Hz,1H),6.95(d,J＝8.2Hz,1H),6.90–6.85(m,1H),4.78(d,J＝8.3Hz,1H),3.88(s,3H),3.81–3.64(m,1H),3.62–3.37(m,3H),3.20–3.06(m,1H),3.05–2.91(m,1H),2.83–2.66(m,1H),2.31–2.16(m,2H),2.14–2.01(m,1H)；13C NMR(101MHz,CD3OD):158.05,133.83,129.49,120.81,119.40,110.28,63.77,56.12,55.04,47.56,32.16,22.48,21.12；HRMS(ESI):calcd for C13H18NO+(M+H)+:204.1383,found 204.1384.
example 20
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000171
Acyl chloride is
Figure BDA0002697425330000172
The chloroamides are
Figure BDA0002697425330000173
2. The experimental results are as follows:
Figure BDA0002697425330000174
the yield is 16%; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):7.00(d,J＝8.4Hz,1H),6.72(d,J＝8.3Hz,1H),6.64(s,1H),4.21–4.11(m,1H),3.88–3.79(m,1H),3.78(s,3H),3.73–3.64(m,1H),3.16–3.09(m,1H),3.06–2.98(m,1H),2.79–2.62(m,2H),2.34–2.13(m,2H)；13C NMR(101MHz,CDCl3):157.82,139.12,130.26,126.98,112.50,111.22,55.31,52.88,42.39,40.23,39.03,28.59；HRMS(ESI):calcd for C12H16NO+(M+H)+:190.1226,found 190.1231.
example 21
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000175
Acyl chloride is
Figure BDA0002697425330000176
The chloroamides are
Figure BDA0002697425330000177
2. The experimental results are as follows:
Figure BDA0002697425330000181
the yield is 85 percent; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):6.55(d,J＝5.6Hz,2H),5.92(s,2H),4.37(s,1H),3.66–3.45(m,3H),3.36–3.20(m,1H),3.18–3.05(m,1H),3.04–2.92(m,1H),2.16–1.95(m,2H),1.86–1.74(m,2H),1.70–1.57(m,2H),1.55–1.37(m,2H)；13C NMR(101MHz,CDCl3):147.38,146.98,125.30,124.79,108.70,106.08,101.27,54.93,44.91,39.39,34.31,32.09,26.55,25.59,24.58；HRMS(ESI):calcd for C15H20NO2 +(M+H)+:246.1489,found 246.1494.
example 22
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000182
Acyl chloride is
Figure BDA0002697425330000183
The chloroamides are
Figure BDA0002697425330000184
2. The experimental results are as follows:
Figure BDA0002697425330000185
the yield is 48 percent; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):7.74(d,J＝7.7Hz,2H),7.38–7.32(m,1H),7.31–7.28(m,1H),7.28–7.21(m,1H),7.20–7.15(m,1H),6.89–6.81(m,1H),6.63(d,J＝7.9Hz,1H),4.36–4.30(m,1H),3.57–3.47(m,1H),3.32–3.04(m,1H),2.62–2.44(m,1H),2.25–2.08(m,3H)；HRMS(ESI):calcd for C16H16N+(M+H)+:222.1277,found 222.1271.
example 23
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000191
Acyl chloride is
Figure BDA0002697425330000192
The chloroamides are
Figure BDA0002697425330000193
2. The experimental results are as follows:
Figure BDA0002697425330000194
the yield is 51 percent; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):8.34(dd,J＝7.9,1.0Hz,1H),7.94–7.81(m,2H),7.59–7.51(m,3H),7.51–7.45(m,2H),4.90(s,1H),3.41–3.26(m,1H),3.23–3.08(m,1H),3.02(td,J＝13.0,2.9Hz,1H),2.82–2.54(m,2H),1.89–1.80(m,1H),1.75–1.64(m,2H)；HRMS(ESI):calcd for C17H18N+(M+H)+:236.1434,found 236.1439.
example 24
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000195
Acyl chloride is
Figure BDA0002697425330000196
The chloroamides are
Figure BDA0002697425330000197
2. The experimental results are as follows:
Figure BDA0002697425330000198
the yield is 79 percent; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3)：7.47(d,J＝7.7Hz,1H),7.27–7.22(m,1H),7.17(t,J＝7.5Hz,1H),7.07(t,J＝7.3Hz,1H),3.65(s,3H),3.64–3.61(m,1H),3.19–3.07(m,2H),2.95–2.88(m,1H),2.85–2.69(m,3H),2.18–2.07(m,1H),1.96–1.87(m,1H),1.84–1.73(m,1H),1.69–1.53(m,3H)；13C NMR(101MHz,CDCl3)：137.81,137.10,126.74,121.00,118.89,118.10,108.74,108.03,58.39,55.86,49.53,31.00,29.14,24.96,23.41,22.19；HRMS(ESI):calcd for C16H21N2 +(M+H)+:241.1699,found 241.1693.
example 25
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2, using the same example 1, wherein the primary amine is
Figure BDA0002697425330000201
Acyl chloride is
Figure BDA0002697425330000202
The chloroamides are
Figure BDA0002697425330000203
2. The experimental results are as follows:
Figure BDA0002697425330000204
the yield is 83 percent; the purity is more than 90 percent; a light yellow oil l;1H NMR(400MHz,CDCl3):1H NMR(400MHz,CDCl3)7.55–7.49(m,1H),7.30–7.18(m,3H),7.12–7.03(m,3H),7.00(d,J＝6.9Hz,2H),5.27(q,J＝17.3Hz,2H),3.55(d,J＝10.2Hz,1H),3.23–3.13(m,1H),3.13–3.06(m,1H),3.03–2.92(m,1H),2.86–2.68(m,3H),1.93–1.83(m,1H),1.82–1.70(m,2H),1.64–1.54(m,1H),1.53–1.47(m,1H),1.46–1.37(m,1H)；13C NMR(101MHz,CDCl3):137.85,137.71,137.24,128.75,127.81,127.20,125.92,121.31,119.29,118.16,109.66,108.83,58.57,56.02,49.63,47.64,29.47,24.99,23.42,22.33；HRMS(ESI):calcd for C22H25N2 +(M+H)+:317.2012,found 317.2008.
example 26
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000211
Acyl chloride is
Figure BDA0002697425330000212
The chloroamides are
Figure BDA0002697425330000213
2. The experimental results are as follows:
Figure BDA0002697425330000214
the yield is 71%; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3):8.04–7.75(m,1H),7.54–7.32(m,3H),5.02(s,1H),3.93–3.70(m,1H),3.59(m,1H),3.52–3.10(m,3H),3.12–2.82(m,2H),2.36–2.01(m,3H)；13C NMR(101MHz,CDCl3):138.41,137.08,130.89,125.59,125.48,121.36,120.00(q,J＝328.25Hz),119.01,115.59,58.21,55.70,45.85,29.32,25.06,22.53；HRMS(ESI):calcd for C15H16F3N2O2S+(M+H)+:345.0879,found 345.0875.
example 27
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000215
Acyl chloride is
Figure BDA0002697425330000216
The chloroamides are
Figure BDA0002697425330000217
2. The experimental results are as follows:
Figure BDA0002697425330000218
the yield is 75%; the purity is more than 90 percent; a light yellow oil;1H NMR(400MHz,CDCl3)7.95(d,J＝6.0Hz,1H),7.47–7.43(m,1H),7.39–7.31(m,2H),3.88(s,1H),3.32–3.18(m,1H),3.17–3.08(m,1H),3.05–2.92(m,1H),2.85–2.72(m,3H),2.23(d,J＝9.3Hz,1H),1.92–1.83(m,1H),1.78–1.70(m,1H),1.65–1.54(m,2H),1.50–1.40(m,1H)；13C NMR(101MHz,CDCl3)136.63,130.29,128.34,127.19,126.17,119.74,119.59(d,J＝328.25Hz),119.40,115.02,58.57,52.19,45.03,31.53,29.67,22.01,17.52；HRMS(ESI):calcd for C16H18F3N2O2S+(M+H)+:359.1036,found 359.1029.
example 28
1. The synthesis steps are as follows: the product of example 26 (69mg,0.2mmol) was dissolved in a mixed solution of 16mL of methanol and 4mL of water. Sodium hydroxide (160mg,4.0mmol) was added and heated under reflux for 2 h. The reaction solution was extracted with dichloromethane (3X 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate for 2 h. Filtering, and concentrating under reduced pressure to remove the solvent. Purifying by column chromatography to obtain 40mg product.
2. The experimental results are as follows:
Figure BDA0002697425330000221
the yield is 95 percent; the purity is more than 90 percent; pale yellow solid, melting point 172-. 1H NMR NMR (400MHz, CDCl)3)8.11(s,1H),7.47(t,J＝15.9Hz,1H),7.30(d,J＝7.7Hz,1H),7.21–6.99(m,1H),4.36–4.20(m,1H),3.42–3.23(m,1H),3.19–3.03(m,1H),2.99–2.86(m,3H),2.78–2.59(m,1H),2.40–2.19(m,1H),2.02–1.76(m,3H).13C NMR(101MHz,CDCl3)136.74,128.14,125.47,122.58,119.72,118.06,111.88,104.97,59.28,51.01,46.59,30.09,22.35,16.92；HRMS(ESI):calcd for C14H17N2 +(M+H)+:213.1386,found 213.1394.
Example 29
1. The synthesis steps are as follows: the product of example 27 (69mg,0.2mmol) was dissolved in a mixed solution of 16mL of methanol and 4mL of water. Sodium hydroxide (160mg,4.0mmol) was added and heated under reflux for 2 h. The reaction solution was extracted with dichloromethane (3X 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate for 2 h. Filtering, and concentrating under reduced pressure to remove the solvent. Purifying by column chromatography to obtain 40mg product.
2. Results of the experiment
Figure BDA0002697425330000222
The yield is 93 percent; the purity is more than 90 percent; pale yellow solid, melting point: 153-.1H NMR(400MHz,CDCl3):7.83(s,1H),7.51(d,J＝7.4Hz,1H),7.34–7.29(m,1H),7.20–7.04(m,2H),3.30–3.22(m,1H),3.14–3.01(m,3H),2.79–2.63(m,2H),2.46–2.38(m,1H),2.11–2.03(m,1H),1.96–1.88(m,1H),1.83–1.72(m,2H),1.67–1.56(m,1H),1.56–1.42(m,1H)；13C NMR(101MHz,CDCl3)136.01,135.15,127.52,121.28,119.36,118.13,110.77,108.11,60.28,55.77,53.58,29.98,25.74,24.33,21.61；HRMS(ESI):calcd for C15H19N2 +(M+H)+:227.1543,found 227.1531.
Example 30
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000231
Acyl chloride is
Figure BDA0002697425330000232
The chloroamides are
Figure BDA0002697425330000233
2. The experimental results are as follows:
Figure BDA0002697425330000234
the yield is 86%; the purity is more than 90 percent; a colorless oil;1H NMR(400MHz,CDCl3):6.60(s,1H),6.56(s,1H),3.84(d,J＝1.9Hz,6H),3.44–3.35(m,1H),3.21–3.12(m,1H),3.10–2.96(m,2H),2.77–2.67(m,1H),2.66–2.49(m,2H),2.36–2.25(m,1H),1.97–1.79(m,2H),1.77–1.65(m,1H)；HRMS(ESI):calcd for C14H20NO2 +(M+H)+:234.1489,found 234.1484.
example 31
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000235
Acyl chloride is
Figure BDA0002697425330000236
The chloroamide is prepared from
Figure BDA0002697425330000237
2. The experimental results are as follows:
Figure BDA0002697425330000238
the yield is 87%; the purity is more than 90 percent; a light yellow oil; 1H NMR (400MHz, CDCl)3):6.56(s,1H),6.54(s,1H),5.88–5.84(m,2H),3.38–3.32(m,1H),3.17–3.11(m,1H),3.09–3.02(m,1H),3.02–2.93(m,1H),2.75–2.67(m,1H),2.63–2.49(m,2H),2.32–2.22(m,1H),1.95–1.80(m,2H),1.73–1.62(m,1H)；HRMS(ESI):calcd for C13H16NO2 +(M+H)+:218.1176,found 218.1173.
Example 32
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000241
Acyl chloride is
Figure BDA0002697425330000242
The chloroamides are
Figure BDA0002697425330000243
2. The experimental results are as follows:
Figure BDA0002697425330000244
the yield is 39%; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,CDCl3):7.36–7.30(m,2H),7.28–7.23(m,1H),7.19(m,4H),7.08(m,1H),6.86(d,J＝7.7Hz,1H),4.43(dd,J＝10.6,6.6Hz,1H),3.59(t,J＝8.0Hz,1H),3.49(dd,J＝11.7,6.5Hz,1H),3.18(m,1H),2.70(t,J＝11.2Hz,1H),2.48(m,2H),2.01–1.91(m,2H),1.84(m,1H)；HRMS(ESI):calcd for C18H20N+(M+H)+:250.1590,found 250.1588
example 33
1. The synthesis steps are as follows: the general formula of the synthetic route is shown in FIG. 2 in the same example 1, wherein the primary amine is
Figure BDA0002697425330000245
Acyl chloride is
Figure BDA0002697425330000246
The chloroamide is prepared from
Figure BDA0002697425330000247
2. The experimental results are as follows:
Figure BDA0002697425330000248
the yield is 45 percent; the purity is more than 90 percent; a yellow oil;1H NMR(400MHz,CDCl3):7.30–7.26(m,1H),7.25(d,J＝2.0Hz,2H),7.24–7.18(m,2H),7.17–7.13(m,2H),7.09–7.04(m,1H),6.91–6.86(m,1H),4.20(t,J＝5.3Hz,1H),3.59(dd,J＝9.6,7.3Hz,1H),3.04(dd,J＝11.0,5.6Hz,1H),2.97(m,1H),2.90(dd,J＝11.0,5.2Hz,1H),2.71–2.62(m,1H),2.42–2.31(m,1H),2.03–1.93(m,1H),1.86(m,2H)；HRMS(ESI):calcd for C18H20N+(M+H)+:250.1590,found250.15733.
in summary, the invention provides a synthesis method of a tetrahydroisoquinolino ring compound and a tetrahydro-beta-carbolino ring compound, which is characterized in that after the halogenated amide with a specific structure is synthesized by the method, the halogenated amide is used as a raw material and is prepared by a one-pot method through intramolecular ring closure reaction and reduction reaction in series. The method has the advantages of easily obtained raw materials, simple steps, high synthesis efficiency, mild reaction conditions, environmental friendliness and strong universality, and provides a new way for synthesizing the tetrahydroisoquinoline tricyclic compound and the tetrahydro-beta-carboline bicyclic compound.

Claims (10)

1. A method for synthesizing tetrahydroisoquinolino ring compounds, comprising the steps of:
(1) reacting primary amine shown in a formula I with acyl halide shown in a formula II under the action of alkali to obtain a compound shown in a formula III;
(2) the halogenated amide shown in the formula III is subjected to amide and aromatic ring dehydration cyclization reaction under the action of an activating agent to obtain a compound shown in the formula IV;
(3) adding a reducing agent into the compound shown in the formula IV to react to obtain a tetrahydroisoquinoline ring-fused compound shown in the formula V;
the reaction route is as follows:
Figure FDA0002697425320000011
wherein n is an integer from 1 to 4; x is halogen; r1And R3Are respectively and independently selected from hydrogen and C1-3An alkoxy group; r2Selected from hydrogen, halogen, C1-3Alkyl, methoxy, t-butyldimethylsilyloxy, acetoxy; or R1And R2Linked to form a 3-5 membered saturated oxacyclyl group; r4、R5Each independently selected from hydrogen, phenyl, or R4And R5Are linked to form a phenyl group.
2. The method of claim 1, wherein R is2Preferably hydrogen, halogen, C1-3Alkyl, t-butyldimethylsiloxy, acetoxy; r4、R5Preferably hydrogen; r1、R2And/or R3Is C1-3When alkoxy, methoxy is preferred; r1And R2When they are bonded to form a 3-to 5-membered saturated oxygen heterocyclic group, the oxygen heterocyclic group is preferably a 5-membered oxygen heterocyclic group having 2 oxygen atoms, more preferably 2 oxygen atoms
Figure FDA0002697425320000012
3. The method of claim 1The method is characterized by further comprising the following steps: when R in the formula III2When the tert-butyldimethylsiloxy group is obtained, adding ethyl acetate saturated hydrogen chloride solution to react at room temperature to remove the tert-butyldimethylsiloxy group to obtain
Figure FDA0002697425320000013
Wherein n is an integer from 1 to 4, R1And R3Are respectively and independently selected from hydrogen and C1-3An alkoxy group; r2Selected from hydrogen, halogen, C1-3Alkyl, methoxy, tert-butyldimethylsilyloxy, acetoxy, R4、R5Each independently selected from hydrogen, phenyl, or R4And R5Are linked to form a phenyl group.
4. A method for synthesizing a tetrahydro-beta-carbolino-cyclic compound is characterized by comprising the following steps:
1) reacting primary amine shown in a formula VI with acyl halide shown in a formula VII under the action of alkali to obtain a compound shown in a formula VIII;
2) the halogenated amide shown in the formula VIII is subjected to amide and aromatic ring dehydration cyclization reaction under the action of an activating agent to obtain a compound shown in the formula IX;
3) adding a reducing agent into the compound shown in the formula IX to react to obtain the tetrahydro-beta-carboline ring-fused compound shown in the formula X, wherein the reaction route is as follows:
Figure FDA0002697425320000021
wherein n is an integer from 1 to 4, and X is halogen; r6Selected from alkyl, benzyl, trifluoromethanesulfonyl.
5. The method of claim 4, further comprising the steps of: when R in formula XII6When the compound is trifluoromethanesulfonyl, sodium hydroxide can be further added, and trifluoromethanesulfonyl can be removed through methanol reflux reaction to obtain trifluoromethanesulfonyl
Figure FDA0002697425320000022
n is an integer from 1 to 4.
6. The process according to any one of claims 1 to 5, wherein the base in step (1) and/or step 1) is selected from at least one of organic bases and inorganic bases, preferably from at least one of triethylamine, pyridine, 2-fluoropyridine, 2-chloropyridine, 2-iodopyridine, 4-dimethylaminopyridine, sodium hydroxide, sodium carbonate and sodium bicarbonate, more preferably triethylamine; in the step (2) and/or the step 2), the activating agent is trifluoromethanesulfonic anhydride and pyridine base; the reducing agent in the step (3) and/or the step 3) is KBH4、NaBH3CN、NaBH(OAc)3、NaBH4Is preferably NaBH4。
7. The process according to claim 6, wherein the pyridine base is selected from 2-chloropyridine, 2-iodopyridine, pyridine, preferably 2-fluoropyridine.
8. The process according to any one of claims 1 to 5, wherein the reaction conditions for the dehydration cyclization of the amide with the aromatic ring in step (2) and/or step 2) are: under the protection of argon, reacting at-90 to-60 ℃ for 25 to 35 minutes, heating to 30 to 50 ℃ and reacting for 1.5 to 2.5 hours or reacting at 110 to 130 ℃ for 15 to 20 minutes; the step (3) and/or the step 3) further comprises the following separation and purification steps: adding saturated sodium bicarbonate solution; extracting with dichloromethane, and mixing organic phases; drying with anhydrous sodium sulfate; filtering, concentrating, and purifying the residue by silica gel column chromatography.
9. The method of claim 8, wherein the reaction conditions for the dehydration cyclization of the amide with the aromatic ring are: reacting at-78 deg.C for 30min under the protection of argon, heating to 40 deg.C, and reacting for 2 hr or at 120 deg.C for 18 min.
10. The method according to any one of claims 1 to 5, wherein the reaction conditions in step (3) and/or step 3) are room temperature reaction for 1.5 to 2.5 hours, preferably room temperature reaction for 2 hours.
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Title
TALK, RUAA A.等: "Synthesis of substituted tetrahydroisoquinolines by lithiation then electrophilic quench", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 *

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