Preparation method of 1-phosphonate group-2-(sulfonyl) acyl-1, 2, 3, 4 tetrahydroisoquinoline compound

Abstract

The invention discloses a preparation method of a 1-phosphonate group-2-(sulfonyl) acyl-1, 2, 3, 4 tetrahydroisoquinoline compound in the technical field of chemistry, and the preparation method comprises the following steps: by taking a compound as shown in a structural general formula I as a raw material, firstly carrying out photooxidation reduction reaction, and then carrying out post-treatment to obtain the 1-phosphonate group-2-(sulfonyl) acyl-1, 2, 3, 4 tetrahydroisoquinoline compound. The preparation method comprises the following steps: firstly, adding alcohol or water as shown in a structural general formula II, protonic acid or lewis acid, phosphite as shown in a structural general formula III and a (sulfonyl) acylation reagent as shown in a structural general formula IV in situ, and then carrying out subsequent multi-component reaction to obtain the 1-phosphonate group-2-(sulfonyl) acyl-1, 2, 3, 4 tetrahydroisoquinoline compound as shown in a structural general formula V; according to the invention, a convenient and efficient new synthesis route is provided for the 1-phosphonate group-2-(sulfonyl) acyl-1, 2, 3, 4 tetrahydroisoquinoline compound.

Description

Technical Field

[0001] The invention belongs to the technical field of chemistry, and particularly relates to a method for preparing 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compounds. Background Art

[0002] α-Acylaminophosphonates are classic bioisosteres of α-amino acids and are an important class of biologically active structures in the pharmaceutical industry. They are widely present in biologically active compounds and natural products. At the same time, this class of structures is also an important class of synthons in organic synthesis. 1-Phosphonate-2-(sulfonate)acyl-1,2,3,4-tetrahydroisoquinoline, as a bioisostere of 1-ester 2-acyl-1,2,3,4-tetrahydroisoquinoline, contains both α-acylaminophosphonate and the dominant skeleton 1,2,3,4-tetrahydroisoquinoline, which may exhibit unique biological activities. Therefore, the development of new and efficient methods to construct novel and diverse 1-phosphonate-2-(sulfonate)acyl-1,2,3,4-tetrahydroisoquinoline compounds is of great significance to enrich the methodology of organic synthesis and deepen the study of chemical biology in this field.

[0003]

[0004] At present, there are still few methods for the synthesis of 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compounds. The first method is to use isoquinoline compounds as substrates and prepare them through aza-Pudovik reactions and reduction reactions (Eur. J. Org. Chem. 2024, 27, e202301212; Chem. Commun. 2022, 58, 9393; Chem. Sci. 2016, 7, 6940.), but this method requires two-step reactions on the one hand, which is less economical; on the other hand, it requires the use of hydrogen and precious metal catalysts, which have safety hazards. The second method is similar to the former, using 3,4-dihydroisoquinoline as a substrate and preparing it through an aza-Pudovik reaction (Commun. Chem. 2023, 6, 26; Synthesis 2020, 52, 769.), but this method requires the pre-preparation of 3,4-dihydroisoquinoline compounds, and the preparation process requires the use of an equivalent amount of oxidant, which is not economical and does not meet the current requirements of green development. The third method is to prepare it with N,O-acetal as a substrate under the catalysis of proton acid or Lewis acid (Org. Biomol. Chem. 2022, 20, 6571; Molecules, 2016, 21, 1140.), but this method requires multi-step reactions to prepare N,O-acetal, and the economy of the reaction and the applicability of the substrate are insufficient. The last method is the direct α-phosphonation reaction of amides, but there is only one electrochemical report (Synlett 2020, 31, 1191.), which requires a specific electrochemical device and may also be insufficient in stability for industrial amplification. At the same time, the above-mentioned reported methods are only applicable to the preparation of 1-phosphonate-2-acyl-1,2,3,4-tetrahydroisoquinoline compounds. There are no reports on the preparation of 1-phosphonate-2-sulfonyl-1,2,3,4-tetrahydroisoquinoline compounds, but the sulfonyl group, as a bioisostere of the acyl group, may have an important influence on the activity of the compound. In addition, the present application compares the preparation method of a 1-cyano-2-substituted 1,2,3,4-tetrahydroisoquinoline compound disclosed in previous patents (CN117586182A and CN117603139A) with the preparation method of a 1-(hetero)aryl-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound, and finds that it is not suitable for the synthesis of 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compounds. Therefore, it is urgent to develop an efficient, green, and universal method to synthesize 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compounds. Summary of the invention

[0005] The present invention aims to provide a method for preparing 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compounds, which has readily available raw materials and is simple to operate.

[0006] A method for preparing a 1-phosphonate-2-(sulfonate)acyl-1,2,3,4-tetrahydroisoquinoline compound in the present scheme comprises the following steps: using a compound represented by a general structural formula of formula I as a raw material, firstly performing a photooxidation-reduction reaction, then in situ adding an alcohol or water represented by a general structural formula of formula II, a protonic acid or a Lewis acid, a phosphite represented by a general structural formula of formula III, and a (sulfonate) acylating agent represented by a general structural formula of formula IV, and then performing a subsequent multi-component reaction to obtain a 1-phosphonate-2-(sulfonate)acyl-1,2,3,4-tetrahydroisoquinoline compound represented by a general structural formula of formula V;

[0007]

[0008] In the general structural formula of formula I and formula V, R 1 , R 2 , R 3 , R 4 Each is independently selected from any one of the following groups: hydrogen atom, fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester group, N,N-disubstituted amino group, C1-C6 straight chain or branched alkyl or cycloalkyl, C1-C6 alkoxy, naphthyl, phenyl and naphthalene or phenyl containing substituents; in the naphthalene or phenyl containing substituents, the substituents are selected from at least one of fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester group, C1-C6 straight chain or branched alkyl or cycloalkyl, C1-C6 alkoxy; in the general formula of formula II, R 5 Any one of the following groups: hydrogen; C1-C6 straight chain or branched alkyl or cycloalkyl, naphthyl, phenyl and the above groups containing substituents; C1-C6 straight chain or branched alkyl or cycloalkyl, naphthyl, phenyl containing substituents, the substituents are selected from at least one of fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester, C1-C6 straight chain or branched alkyl or cycloalkyl, C1-C6 alkoxy; in the general formula of formula III and the general formula of formula V, R 6 Any one of the following groups: C1-C6 straight chain or branched alkyl or cycloalkyl, naphthyl, phenyl and the above groups containing substituents; C1-C6 straight chain or branched alkyl or cycloalkyl, naphthyl, phenyl containing substituents, the substituents are selected from at least one of fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester, C1-C6 straight chain or branched alkyl or cycloalkyl, C1-C6 alkoxy; in the general formula IV and the general formula V, R 7Any one selected from the following groups: C1-C6 straight chain or branched alkyl or cycloalkyl, naphthyl, phenyl and the above groups containing substituents; among the C1-C6 straight chain or branched alkyl or cycloalkyl, naphthalene and phenyl containing substituents, the substituents are selected from at least one of fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester, N,N-disubstituted amino, C1-C6 straight chain or branched alkyl or cycloalkyl, and C1-C6 alkoxy; the acid is a protonic acid or a Lewis acid.

[0009] Further, the protonic acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid; the Lewis acid is ferrous trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, copper trifluoromethanesulfonate, zirconium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, boron trifluoride, ferrous chloride, ferrous sulfate or ferrous acetate, preferably ferrous trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate.

[0010] Furthermore, the photosensitizer is a porphyrin photosensitizer, an Eosin Y photosensitizer, an Ir(ppy)3 photosensitizer, or a Ru(bpy)3Cl2 photosensitizer, preferably a porphyrin photosensitizer.

[0011] Furthermore, the oxidant is hydrogen peroxide, tert-butyl peroxide, iodosylbenzene, m-chloroperbenzoic acid, diacetoxy iodobenzene, oxygen or air, preferably air or oxygen.

[0012] Further, the desiccant is Molecular sieves, Molecular sieves, Molecular sieve, anhydrous sodium sulfate or anhydrous magnesium sulfate. or Molecular sieve.

[0013] Furthermore, the illumination is blue light, purple light or white light, with a wattage of 4 watts to 50 watts. Preferably, the illumination is blue light, with a wattage of 8 watts to 24 watts;

[0014] Furthermore, the solvent is selected from at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide and acetonitrile. 1,4-dioxane is preferred; the amount of the solvent is 0.05mL-10.0mL, preferably 0.2mL-1.0mL, per 0.1 mmol of the compound represented by the general structural formula of formula I.

[0015] Furthermore, the photo-oxidation-reduction reaction temperature is -20°C to 110°C, and the reaction time is 1 hour to 120 hours. Preferably, the photo-oxidation-reduction reaction temperature is 0°C to 40°C, and the reaction time is 4 hours to 48 hours.

[0016] Furthermore, the multi-component reaction temperature is 0°C to 110°C, and the reaction time is 0.5 hours to 120 hours. Preferably, the multi-component reaction temperature is 15 to 40°C, and the reaction time is 1 hour to 12 hours.

[0017] Further, the amount of the photosensitizer is 0.1%-100% of the molar amount of the compound represented by the general formula of the structure of formula I; the amount of the desiccant is 1mg-200mg of the desiccant for every 0.1 mmol of the compound represented by the general formula of the structure of formula I; the molar ratio of the compound represented by the general formula of the structure of formula II to the compound represented by the general formula of the structure of formula I is 0.5:1.0-4.0:1.0; the molar ratio of the proton acid or Lewis acid to the compound represented by the general formula of the structure of formula I is 0.01:1.0-1.0:1.0; the molar ratio of the compound represented by the general formula of the structure of formula III to the compound represented by the general formula of the structure of formula I is For example, it is 0.5:1.0-5.0:1.0; the molar ratio of the compound represented by the general formula of formula IV to the compound represented by the general formula of formula I is 0.5:1.0-5.0:1.0; the amount of the solvent used is 0.05mL-10.0mL of solvent for every 0.1 millimole of the compound represented by the general formula of formula I; when the oxidant is air or oxygen, air or oxygen balloon is used; when the oxidant is hydrogen peroxide, tert-butyl peroxide, iodosylbenzene, m-chloroperbenzoic acid or diacetoxyiodobenzene, the amount of the oxidant used is 10%-400% of the molar amount of the compound represented by the general formula of formula I.

[0018] Further, the amount of the photosensitizer is 1-20% of the molar amount of the compound represented by the general formula of the structure of formula I; the amount of the desiccant is 10 mg-100 mg of the desiccant for every 0.1 mmol of the compound represented by the general formula of the structure of formula I; the molar ratio of the compound represented by the general formula of the structure of formula II to the compound represented by the general formula of the structure of formula I is 0.8:1.0-2.0:1.0; the molar ratio of the proton acid or Lewis acid to the compound represented by the general formula of the structure of formula I is 0.1:1.0-0.3:1.0; the molar ratio of the compound represented by the general formula of the structure of formula III to the compound represented by the general formula of the structure of formula I The molar ratio of the compounds shown in the general formula is 1.0:1.0-2.0:1.0; the molar ratio of the compound shown in the general formula of the structure IV to the compound shown in the general formula of the structure I is 1.0:1.0-2.0:1.0; the amount of the solvent used is 0.2mL-1.0mL of the solvent for every 0.1 mmol of the compound shown in the general formula of the structure I; when the oxidant is hydrogen peroxide, tert-butyl peroxide, iodosylbenzene, m-chloroperbenzoic acid or diacetoxyiodobenzene, the amount of the oxidant used is 50-200% of the molar amount of the compound shown in the general formula of the structure I.

[0019] The invention has the following beneficial effects: using easily available 1,2,3,4-tetrahydroisoquinoline compounds, phosphites and (sulfonated) acylating agents as raw materials; under light irradiation, air can be used as an oxidant, and the environment is highly friendly; through a light-mediated "one-pot" multi-component cascade reaction, the bifunctionalization reaction of 1-phosphonate esterification and 2-(sulfonated) acylation of 1,2,3,4-tetrahydroisoquinoline is directly realized, the reaction conditions are mild, the operation is simple, the atom and step economy is high, and the product structure types are diverse, thereby providing a convenient and efficient new synthesis route for 1-phosphonate-2-(sulfonated) acyl-1,2,3,4-tetrahydroisoquinoline compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The compound of formula Va prepared in Example 1 of the present invention 1 H-NMR spectrum;

[0021] Figure 2 The compound of formula Vb prepared in Example 2 of the present invention 1 H-NMR spectrum;

[0022] Figure 3 The compound of formula Vc prepared in Example 3 of the present invention 1 H-NMR spectrum;

[0023] Figure 4 The compound of formula Vd prepared in Example 4 of the present invention 1 H-NMR spectrum;

[0024] Figure 5 The compound of formula Ve prepared in Example 5 of the present invention 1 H-NMR spectrum;

[0025] Figure 6 The compound of formula Vf prepared in Example 6 of the present invention 1 H-NMR spectrum;

[0026] Figure 7 The compound of formula Vg prepared in Example 7 of the present invention 1 H-NMR spectrum;

[0027] Figure 8 The compound of formula Vh prepared in Example 8 of the present invention 1 H-NMR spectrum;

[0028] Fig. 9 The compound of formula Vi prepared in Example 9 of the present invention 1 H-NMR spectrum;

[0029] Fig.10 The compound of formula Vj prepared in Example 10 of the present invention 1H-NMR spectrum;

[0030] Fig.11 The compound of formula Vk prepared in Example 11 of the present invention 1 H-NMR spectrum;

[0031] Fig.12 The compound of formula V1 prepared in Example 12 of the present invention 1 H-NMR spectrum;

[0032] Fig.13 The compound of formula Vm prepared in Example 13 of the present invention 1 H-NMR spectrum;

[0033] Fig.14 The compound of formula Vn prepared in Example 14 of the present invention 1 H-NMR spectrum;

[0034] Fig.15 The compound of formula Vo prepared in Example 15 of the present invention 1 H-NMR spectrum;

[0035] Fig.16 The compound of formula Vp prepared in Example 16 of the present invention 1 H-NMR spectrum;

[0036] Fig.17 The compound of formula Vq prepared in Example 17 of the present invention 1 H-NMR spectrum;

[0037] Fig.18 The compound of formula Vr prepared in Example 18 of the present invention 1 H-NMR spectrum. DETAILED DESCRIPTION

[0038] The present invention is further described below in conjunction with specific examples, but the present invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The reactants can be obtained from public commercial channels unless otherwise specified.

[0039] Hereinafter, similar methods refer to methods in which the reaction conditions are the same except for the differences in the corresponding substances in the reaction formula.

[0040] Example 1, Preparation of the compound represented by the structure of formula Va

[0041] The reaction formula is as follows

[0042]

[0043] 1,2,3,4-Tetrahydroisoquinoline (0.500 mmol), meso-tetrakis(2,4,6-trimethylphenyl)porphyrin (0.010 mmol), Molecular sieves (0.250 g) and 1,4-dioxane (2.5 mL) were added to the reaction bottle, and then an air ball was connected, and the reaction was carried out at room temperature under 12 watts of blue light. After 12 hours, the blue light was removed, and water (0.750 mmol), ferrous trifluoromethanesulfonate (0.100 mmol), triethyl phosphite (1.000 mmol) and p-toluenesulfonyl chloride (0.600 mmol) were added to the above reaction, and the reaction was carried out at room temperature after the addition was completed. After 4 hours, the reaction solution was filtered through diatomaceous earth, and the filtrate was dried and separated by silica gel column chromatography to obtain 178 mg of the compound shown in the structure of formula Va, with a yield of 84%.

[0044] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.60(d,J=8.1Hz,2H),7.34(d,J=7.2Hz,1H),7.21–7.03(m,4H),6.89(d,J=7.2Hz,1H),5.51(d,J=24.6Hz,1H),4.24–3. 95(m,5H),3.85(dd,J=14.5,6.5Hz,1H),2.62(d,J=16.8Hz,1H),2.52–2.39(m,1H),2.33(s,3H),1.32(t,J=7.0Hz,3H),1.25(t,J=7.0Hz,3H).

[0045] Example 2, Preparation of the compound represented by the structural formula Vb

[0046] The reaction formula is as follows:

[0047]

[0048] The compound of formula Vb was prepared in a similar manner as described in Example 1 to obtain 129 mg of the compound with a yield of 53%. 1H NMR(400MHz, CDCl3) δ7.89(s,1H),7.66(d,J=7.9Hz,1H),7.57(d,J=8.0Hz,1H),7 .34(d,J=7.1Hz,1H),7.20(t,J=7.9Hz,1H),7.18–7.10(m,2H),6.93(d,J=7.0Hz,1 H),5.48(d,J=24.5Hz,1H),4.28–3.97(m,5H),3.87(dd,J=14.3,6.8Hz,1H),2.71( d,J=17.0Hz,1H),2.64–2.48(m,1H),1.31(t,J=7.1Hz,3H),1.25(t,J=7.0Hz,3H).

[0049] Example 3, Preparation of the compound represented by the structural formula Vc

[0050] The reaction formula is as follows:

[0051]

[0052] The compound of formula Vc was prepared in a similar manner as described in Example 1 to obtain 140 mg of the compound with a yield of 62%. 1 H NMR(400MHz, CDCl3)δ7.52(d,J=8.5Hz,1H),7.46(s,1H),7.34(d,J=7.0Hz,1H),7.19–7.0 6(m,2H),6.90(d,J=6.7Hz,1H),6.66(d,J=8.4Hz,1H),5.50(d,J=24.9Hz,1H),4.65–4.52 (m,2H),4.22–3.97(m,5H),3.83(dd,J=14.7,6.8Hz,1H),3.19–3.06(m,1H),3.07–2.90(m ,1H),2.71–2.56(m,1H),2.52–2.35(m,1H),1.33(t,J=7.1Hz,3H),1.27(t,J=7.0Hz,3H).

[0053] Example 4, Preparation of the compound represented by the structural formula Vd

[0054] The reaction formula is as follows:

[0055]

[0056] The compound represented by formula Vd was prepared by a similar method as described in Example 1 to obtain 158 mg of the compound with a yield of 72%.

[0057] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.64 (d, J=8.8Hz, 2H), 7.34 (d, J=

[0058] 7.3Hz,1H),7.19–7.05(m,2H),6.90(d,J=7.2Hz,1H),6.78(d,J=8.8Hz,2H),5.50(d,J=24.8Hz,1H),4.23–3.92(m,5H),3.84( dd,J=14.5,6.6Hz,1H),3.78(s,3H),2.62(d,J=16.6Hz,1H),2.52–2.39(m,1H),1.32(t,J=7.1Hz,3H),1.26(t,J=7.1Hz,3H).

[0059] Example 5, Preparation of the compound represented by the structural formula Ve

[0060] The reaction formula is as follows:

[0061]

[0062] The compound represented by formula Ve was prepared by a similar method as described in Example 1 to obtain 129 mg of the compound with a yield of 57%.

[0063] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.40 (d, J=5.0Hz, 1H), 7.24–7.15

[0064] (m,2H),7.11–7.04(m,1H),6.92(s,2H),5.15(d,J=23.2Hz,1H),4.07–3.92(m,3H),3.92–3.78(m,3H),2.88– 2.77(m,1H),2.71(d,J=16.6Hz,1H),2.55(s,6H),2.29(s,3H),1.24(t,J=7.0Hz,3H),1.12(t,J=7.1Hz,3H).

[0065] Example 6, Preparation of the compound represented by the structural formula Vf

[0066] The reaction formula is as follows:

[0067]

[0068] The compound of formula Vf was prepared in a similar manner as described in Example 1 to obtain 140 mg of the compound with a yield of 61%. 1 H NMR (400MHz, CDCl3) δ8.36(s,1H),7.84(d,J=7.8Hz,1H),7.80(d,J=8.0Hz,1H),7.74(d,J=8 .7Hz,1H),7.67–7.51(m,3H),7.38(d,J=7.5Hz,1H),7.13(t,J=7.4Hz,1H),7.05(t,J=7.5Hz ,1H),6.81(d,J=7.5Hz,1H),5.62(d,J=24.4Hz,1H),4.27–3.97(m,5H),3.92(dd,J=14.4,6. 7Hz,1H),2.69–2.55(m,1H),2.51–2.37(m,1H),1.32(t,J=7.1Hz,3H),1.23(t,J=7.1Hz,3H).

[0069] Example 7, Preparation of the compound represented by the structural formula Vg

[0070] The reaction formula is as follows:

[0071]

[0072] The compound of formula Vg was prepared by a similar method as described in Example 1 to obtain 142 mg of brotamers with a yield of 66%. 1 H NMR (400MHz, CDCl3) δ7.57 (d, J=7.0Hz, 1H), 7.51–7.40 (m, 1H), 7.40–7.29 (m,2H),7.25–7.18(m,3H),7.17–7.05(m,1H),6.33(d,J=21.1Hz,1H),4.2 6–4.06(m,3H),4.01–3.86(m,2H),3.81–3.65(m,1H),3.09–2.85(m,1H),2 .79–2.62(m,1H),2.41–1.97(m,3H),1.35–1.28(m,3H),1.23–1.15(m,3H).

[0073] Example 8, Preparation of the compound represented by the structural formula Vh

[0074] The reaction formula is as follows:

[0075]

[0076] The compound represented by formula Vh was prepared by a similar method as described in Example 1 to obtain 141 mg of the compound with a yield of 70%.

[0077] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.55 (d, J=6.6Hz, 1H), 7.36 (t, J=

[0078] 7.9Hz,1H),7.27–7.19(m,2H),7.13(d,J=6.2Hz,1H),7.02–6.97(m,2H),6.97–6.92(m,1H),6.36and 5.30(2d,J=22.0Hz,1H),4.29–4.07(m,3H),4.06–3.85(m,3H),3.83and 3.79(2s,1H),2.98–2.83(m,1H),2.77(d,J=16.5Hz,1H),1.34(t,J=7.1Hz,3H),1.19(t,J=7.1Hz,3H).

[0079] Example 9, Preparation of the compound represented by the structural formula Vi

[0080] The reaction formula is as follows:

[0081]

[0082] The compound of formula Vi was prepared by a similar method as described in Example 1 to obtain 167 mg of the compound with a yield of 74%.

[0083] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.59 (d, J=8.2Hz, 2H), 7.54 (d, J=

[0084] 6.6Hz,1H),7.32(d,J=8.2Hz,2H),7.27–7.20(m,2H),7.13(d,J=6.1Hz,1H),6.33and 5.17(2d,J=21.7Hz,1H),4.23–3.94(m,5H),3.89–3.78(m,1H),3.00–2.73(m,2H),1.32(t,J=7.1Hz,3H),1.19(t,J=7.0Hz,3H).

[0085] Example 10, Preparation of the compound represented by the structural formula Vj

[0086] The reaction formula is as follows:

[0087]

[0088] The compound represented by formula Vj was prepared by a similar method as described in Example 1 to obtain 137 mg of the compound with a yield of 85%.

[0089] The mixture of rotamers: 1 H NMR(400MHz, CDCl3)δ7.47–7.33(m,1H),7.24–7.05(m,3H),6.79–6.56(m,1H),6.38–6.28(m,1H),6.23and 5.33(2d,J=21.0Hz,1H),5.77–5.69(m,1H),4.17–3.92(m,5H),3.91–3.77(m,1H),3.63–3 .50(m,1H),3.06–2.83(m,2H),1.28(dt,J=14.0,4.6Hz,3H),1.14(dt,J=17.0,7.1Hz,3H).

[0090] Example 11, Preparation of the compound represented by the structural formula Vk

[0091] The reaction formula is as follows:

[0092]

[0093] The compound of formula Vk was prepared by a similar method as described in Example 1 to obtain 116 mg of the compound with a yield of 61%. 1 H NMR (400MHz, CDCl3) δ7.53–7.40(m,1H),7.26–7.16(m,2H),7.16–7.08(m,1H),6.24(d, J=21.5Hz,1H) / 5.29(d,J=20.4Hz,1H),4.13–3.99(m,4H),3.94–3.84(m,1H) / 3.84–3.7 3(m,1H),3.07–2.77(m,2H),2.60(t,J=11.6Hz,1H),1.89–1.76(m,3H),1.75–1.64(m,2 H),1.62–1.47(m,2H),1.39–1.22(m,7H),1.17(t,J=7.0Hz,3H) / 1.11(t,J=7.1Hz,1H).

[0094] Example 12, Preparation of the compound represented by the structural formula V1

[0095] The reaction formula is as follows:

[0096]

[0097] The compound represented by formula V1 was prepared by a similar method as described in Example 1 to obtain 236 mg with a yield of 96%.

[0098] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.86–7.66(m,2H),7.64–7.54(m,2H),7.50–7.25(m,5H),7.25–7.17(m,2H),7.18–7.08(m,1H),5.72and 5.38(2d,J=20.5Hz,1H),4.64and 4.51(2dd,J=10.6,6.3Hz,1H),4.40(td,J=10.3,6.9Hz,1H),4.26(dt,J=12.7,6.5Hz,1H),4.19–4.03(m,3H),4.00–3.90and 3.66–3.58(2m,1H),3.86–3.76(m,1H),3.02–2.75(m,2H),1.29–1.21(m,3H),1.16and 1.09(2t,J=7.0Hz,3H).

[0099] Example 13, Preparation of the compound represented by the structural formula Vm

[0100] The reaction formula is as follows:

[0101]

[0102] The compound of formula Vm was prepared in a similar manner as described in Example 1 to obtain 93 mg of the compound with a yield of 41%. 1 H NMR(400MHz, CDCl3) δ7.56(d,J=8.3Hz,2H),7.14–7.03(m,3H),6.94(d,J=7.8Hz,1H),6.62(d,J=8.1Hz,1H),5.47(d,J=24.9Hz,1H),4.23–3.9 8(m,4H),3.98–3.87(m,2H),3.68(s,3H),2.53(d,J=17.6Hz,1H),2.30( s,3H),2.24–2.09(m,1H),1.31(t,J=7.1Hz,3H),1.24(t,J=7.0Hz,3H).

[0103] Example 14, Preparation of the compound represented by the structural formula Vn

[0104] The reaction formula is as follows:

[0105]

[0106] The compound represented by formula Vn was prepared by a similar method as described in Example 1 to obtain 99 mg of the compound with a yield of 41%.

[0107] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.81 (d, J=8.1Hz, 1H), 7.66–7.55

[0108] (m,3H),7.45(dd,J=8.2,1.7Hz,1H),7.12(d,J=8.1Hz,2H),5.55(d,J=25.8Hz,1H),4.24–4.06(m,4H),4.04–3.96(m,1H),3.92(d ,J=6.7Hz,1H),3.88(s,3H),2.66(d,J=16.9Hz,1H),2.54–2.41(m,1H),2.33(s,3H),1.33(t,J=7.1Hz,3H),1.26(t,J=7.1Hz,3H).

[0109] Example 15, Preparation of the compound represented by the structural formula Vo

[0110] The reaction formula is as follows:

[0111]

[0112] The compound of formula Vo was prepared in a similar manner as described in Example 1 to obtain 111 mg of the compound with a yield of 44%. 1 H NMR (400MHz, CDCl3) δ7.60(d,J=8.3Hz,2H),7.34(d,J=7.9Hz,1H),7.09(d,J=8.0Hz ,2H),6.96(td,J=7.7,1.9Hz,1H),6.89(d,J=7.4Hz,1H),5.87(d,J=23.9Hz,1H),4.4 3–4.31(m,2H),4.13–3.95(m,2H),3.95–3.80(m,1H),3.65–3.50(m,1H),3.33–3.20( m,1H),2.66–2.54(m,1H),2.29(s,3H),1.42(t,J=7.0Hz,3H),1.19(t,J=7.1Hz,3H).

[0113] Example 16, Preparation of the compound represented by the structural formula Vp

[0114] The reaction formula is as follows:

[0115]

[0116] The compound represented by formula Vp was prepared by a similar method as described in Example 1 to obtain 113 mg of the compound with a yield of 57%.

[0117] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.61 (d, J=8.3Hz, 2H), 7.34 (d, J=

[0118] 7.4Hz,1H),7.19–7.09(m,4H),6.91(d,J=7.1Hz,1H),5.54(d,J=24.4Hz,1H),4.01–3.92(m,1H), 3.89–3.82(m,1H),3.76(s,3H),3.74(s,3H),2.68–2.60(m,1H),2.53–2.42(m,1H),2.33(s,3H).

[0119] Example 17, Preparation of the compound represented by the structural formula Vq

[0120] The reaction formula is as follows:

[0121]

[0122] The compound represented by formula Vq was prepared by a similar method as described in Example 1 to obtain 158 mg of the compound with a yield of 61%.

[0123] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=8.3Hz, 2H), 7.53–7.46

[0124] (m,1H),7.31–7.21(m,5H),7.20–7.16(m,2H),7.14–7.08(m,3H),7.07–7.01(m,2H),7.01–6.92(m,3H),5.96 (d,J=24.9Hz,1H),4.11–3.97(m,1H),3.94–3.86(m,1H),2.77–2.67(m,1H),2.67–2.55(m,1H),2.31(s,3H).

[0125] Example 18, Preparation of the compound represented by the structural formula Vr

[0126] The reaction formula is as follows:

[0127]

[0128] The compound represented by formula Vr was prepared by a similar method as described in Example 1 to obtain 122 mg of the compound with a yield of 51%.

[0129] The mixture of rotamers: 1 H NMR (400MHz, CDCl3) δ7.60 (d, J = 8.1Hz, 2H), 7.37–7.31

[0130] (m,1H),7.21–7.01(m,4H),6.88(d,J=7.0Hz,1H),5.52(d,J=24.4Hz,1H),4.18– 3.93(m,5H),3.85(dd,J=14.3,6.5Hz,1H),2.61(d,J=17.0Hz,1H),2.52–2.38(m, 1H),2.32(s,3H),1.69–1.61(m,2H),1.60–1.50(m,2H),1.39(dd,J=15.2,7.5Hz ,2H),1.32(dd,J=15.0,7.5Hz,2H),0.92(t,J=7.5Hz,3H),0.88(t,J=7.5Hz,3H).

[0131] Comparative Example: Referring to the disclosed method (CN117586182A and CN117603139A), the compound shown in formula Va was prepared

[0132] The reaction formula is as follows:

[0133]

[0134] 1,2,3,4-Tetrahydroisoquinoline (0.500 mmol), meso-tetrakis(2,4,6-trimethylphenyl)porphyrin (0.015 mmol), Molecular sieves (0.250 g) and toluene (2.5 mL) were added to the reaction bottle, and then an air ball was connected, and the reaction was carried out at room temperature under 12 watts of white light. After 12 hours, the white light was removed, and triethyl phosphite (0.750 mmol) and p-toluenesulfonyl chloride (0.600 mmol) were added to the above reaction, and the temperature was raised to 80 ° C for reaction after the addition. After 12 hours, the reaction solution was filtered through diatomaceous earth, and the filtrate was dried and subjected to silica gel column chromatography, but the compound shown in the structure of formula Va was not isolated. Therefore, the experimental results show that the above-mentioned disclosed method is not suitable for the preparation of 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compounds.

[0135] The above is only an embodiment of the present invention, and the common knowledge in the scheme is not described in detail. It should be pointed out that for those skilled in the art, several modifications and improvements can be made without departing from the structure of the present invention, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent.

Claims

1. A method for preparing 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compounds, Features: The following steps are involved: The compound represented by the general structural formula of formula I is used as a raw material, a photo-oxidation-reduction reaction is first carried out, and then an alcohol or water represented by the general structural formula of formula II, a protonic acid or a Lewis acid, a phosphite represented by the general structural formula of formula III, and a (sulfonated) acylating agent represented by the general structural formula of formula IV are added in situ, and then a subsequent multi-component reaction is carried out to obtain a 1-phosphonate-2-(sulfonated)acyl-1,2,3,4-tetrahydroisoquinoline compound represented by the general structural formula of formula V; In the general structural formula of formula I and formula V, R 1 , R 2 , R 3 , R 4 Each independently selected from any one of the following groups: hydrogen atom, fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester group, N,N-disubstituted amino group, C 1 -C 6 Straight or branched alkyl or cycloalkyl, C 1 -C 6 Alkoxy, naphthyl, phenyl and naphthalene or phenyl containing a substituent; in the naphthalene or phenyl containing a substituent, the substituent is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester, C 1 -C 6 Straight or branched alkyl or cycloalkyl, C 1 -C 6 At least one of the alkoxy groups; in the general structure of formula II, R 5 Any one selected from the following groups: hydrogen; C 1 -C 6 Straight-chain or branched alkyl or cycloalkyl, naphthyl, phenyl and the above groups containing substituents; C 1 -C 6 In a straight chain or branched chain alkyl or cycloalkyl, naphthyl, or phenyl group, the substituent is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester, C 1 -C 6 Straight or branched alkyl or cycloalkyl, C 1 -C 6 At least one of the alkoxy groups; in the general structural formula of formula III and the general structural formula of formula V, R 6 Any one selected from the following groups: C 1 -C 6 Straight-chain or branched alkyl or cycloalkyl, naphthyl, phenyl and the above groups containing substituents; C 1 -C 6 In a straight chain or branched chain alkyl or cycloalkyl, naphthyl, or phenyl group, the substituent is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester, C 1 -C 6 Straight or branched alkyl or cycloalkyl, C 1 -C 6 At least one of the alkoxy groups; in the general structural formula IV and the general structural formula V, R 7 Any one selected from the following groups: C 1 -C 6 Straight-chain or branched alkyl or cycloalkyl, naphthyl, phenyl and the above groups containing substituents; C 1 -C 6 In a straight chain or branched alkyl or cycloalkyl, naphthalene, or phenyl group, the substituent is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoromethyl, nitro, cyano, ester, N,N-disubstituted amino, C 1 -C 6 Straight or branched alkyl or cycloalkyl, C 1 -C 6 At least one of the alkoxy groups; the acid is a protonic acid or a Lewis acid.

2. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 1, Features: The proton acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid; the Lewis acid is ferrous trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, copper trifluoromethanesulfonate, zirconium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, boron trifluoride, ferrous chloride, ferrous sulfate or ferrous acetate.

3. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 2, Features: The photosensitizer is a porphyrin photosensitizer, an Eosin Y photosensitizer, an Ir(ppy) 3 Photosensitizer or Ru(bpy) 3 Cl 2 Photosensitizer type.

4. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 3, Features: The oxidant is hydrogen peroxide, tert-butyl peroxide, iodosobenzene, m-chloroperbenzoic acid, diacetoxyiodobenzene, oxygen or air.

5. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 4, Features: The desiccant is Molecular sieves, Molecular sieves, Molecular sieves, anhydrous sodium sulfate or anhydrous magnesium sulfate.

6. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 5, Features: The light is blue light, purple light or white light, and the wattage is 4 watts to 50 watts.

7. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 6, Features: The solvent is selected from at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide and acetonitrile.

8. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 7, Features: The photo-oxidation-reduction reaction temperature is -20°C to 110°C, and the reaction time is 1 hour to 120 hours; the multi-component reaction temperature is 0°C to 110°C, and the reaction time is 0.5 hour to 120 hours.

9. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 8, Features: The amount of the photosensitizer is 0.1%-100% of the molar amount of the compound of the general structural formula of formula I; the amount of the desiccant is 1mg-200mg per 0.1 mmol of the compound of the general structural formula of formula I; the molar ratio of the compound of the general structural formula of formula II to the compound of the general structural formula of formula I is 0.5:1.0-4.0:1.0; the molar ratio of the protonic acid or Lewis acid to the compound of the general structural formula of formula I is 0.01:1.0-1.0:1.0; the molar ratio of the compound of the general structural formula of formula III to the compound of the general structural formula of formula I is 0.5:1.0-5.0:1.0; the molar ratio of the compound represented by the general structural formula IV to the compound represented by the general structural formula I is 0.5:1.0-5.0:1.0; the amount of the solvent used is 0.05mL-10.0mL of solvent for every 0.1 millimole of the compound represented by the general structural formula I; when the oxidant is air or oxygen, air or an oxygen balloon is used; when the oxidant is hydrogen peroxide, tert-butyl peroxide, iodosylbenzene, m-chloroperbenzoic acid or diacetoxyiodobenzene, the amount of the oxidant used is 10%-400% of the molar amount of the compound represented by the general structural formula I.

10. A method for preparing a 1-phosphonate-2-(sulfonyl)-1,2,3,4-tetrahydroisoquinoline compound according to claim 9, Features: The amount of the photosensitizer is 1-20% of the molar amount of the compound of the general structural formula of formula I; the amount of the desiccant is 10 mg-100 mg of desiccant for every 0.1 mmol of the compound of the general structural formula of formula I; the molar ratio of the compound of the general structural formula of formula II to the compound of the general structural formula of formula I is 0.8:1.0-2.0:1.0; the molar ratio of the proton acid or Lewis acid to the compound of the general structural formula of formula I is 0.1:1.0-0.3:1.0; the molar ratio of the compound of the general structural formula of formula III to the compound of the general structural formula of formula I The molar ratio of the compounds shown is 1.0:1.0-2.0:1.0; the molar ratio of the compound shown in the general structural formula of formula IV to the compound shown in the general structural formula of formula I is 1.0:1.0-2.0:1.0; the amount of the solvent used is 0.2mL-1.0mL of solvent for every 0.1 mmol of the compound shown in the general structural formula of formula I; when the oxidant is hydrogen peroxide, tert-butyl peroxide, iodosylbenzene, m-chloroperbenzoic acid or diacetoxyiodobenzene, the amount of the oxidant used is 50-200% of the molar amount of the compound shown in the general structural formula of formula I.

Images