A process for the preparation of a beta-amino-alpha-diazo derivative

Abstract

The application discloses a preparation method of a beta-amino-alpha-diazo derivative and belongs to the technical fields of medical intermediates and organic synthesis. The alpha-diazo carbonyl compound and the amine compound are used as raw materials, dichloromethane is used as a carbon source, a three-component coupling reaction occurs under the action of alkali in an air atmosphere, and a beta-amino-alpha-diazo derivative is generated. The method has very wide substrate adaptability, the starting raw materials of the reaction are cheap and easy to obtain, the reaction process is simple to operate, is suitable for large-scale synthesis, and can also provide a new method and a new target for the synthesis and modification of drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of β-amino-α-diazo derivative, belongs to the field of pharmaceutical intermediates and organic synthesis. BACKGROUND

[0002] Diazocompounds as a class of important organic compounds can undergo a variety of chemical transformations, and have been widely used in the fields of drug development, new material creation, etc. Natural diazocompounds have intrinsic anti-tumor and anti-bacterial activities, and have potential clinical application value. For example, Lomaiviticin A has anti-tumor activity at sub-micromolar concentrations (He, H., Ding, W.-D., Bernan, V. S., Richardson, A. D., Ireland, C. M., Greenstein, M., Ellestad, G. A., and Carter, G. T. (2001) Lomaiviticins A and B, potent antitumor antibiotics from Micro-monospora lomaivitiensis. J. Am. Chem. Soc. 123, 5362-5363); Kinamycin D has antibacterial activity against Gram-positive bacteria (Ito, S., Matsuya, T., Omura, S., Otani, M., Nakagawa, A., Takeshima, H., Iwai, Y., Ohtani, M., and Hata, T. (1970) A new antibiotic, kinamycin. J. Antibiot. 23, 315-317); azaserine can be used as an antibiotic to inhibit the development of certain tumors (Fusari, S. A., Haskell, T. H., Frohardt, R. P., and Bartz, Q. R. (1954) Azaserine, a new tumor-inhibitory substance. Structural studies. J. Am. Chem. Soc. 76, 2881-2883); 6-diazo-5-oxo-L-norleucine (DON) has beneficial activity against various cancers, lymphomas and Hodgkin's disease (Rahman, A., Smith, F. P., Luc, P.-V., and Woolley, P. V. (1985) Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON). Invest. New Drugs 3, 369-374.), etc.

[0003] The diazo compound is also a multifunctional intermediate in organic synthetic chemistry, but the directly available diazo compounds in nature are rare. At present, although the synthesis method of the diazo compound has been greatly developed, there are defects such as complicated operation, harsh reaction conditions, difficult to obtain raw materials, environmental pollution of heavy metal catalysts and troublesome post-processing. Therefore, it is necessary to develop a safe, efficient, clean, simple and low-cost method for synthesizing the diazo compound. In the reported three-component reaction, the imine generated by the reaction of amine and aldehyde is usually coupled with a nucleophile to generate a target product. Based on this, the present application uses cheap and easily available dichloromethane compound and amine to generate imine by C-halogen and N-H activation coupling, and then reacts with the nucleophile alpha-diazo carbon-based compound, so as to successfully obtain beta-amino-alpha-diazo derivative. SUMMARY

[0004] In view of the above-mentioned defects of the prior art, the present application develops a new method for preparing beta-amino-alpha-diazo derivative with the advantages of simple and easily available raw materials, no need for inert gas protection, simple operation, avoidance of use of noble metal and low cost. The specific steps are as follows: alpha-diazo carbonyl compound, amine compound, base and dichloromethane are added into a reactor, and the reaction is carried out under air atmosphere. After the reaction product is concentrated, it is separated and purified by column chromatography, and then dried to obtain beta-amino-alpha-diazo derivative. The structural formula of the beta-amino-alpha-diazo derivative is shown as formula I and formula II:

[0005]

[0006] wherein R 1 , R 2 is selected from one of alkyl, cycloalkyl, alkoxy, phenyl or benzyl, R 3 is selected from one of alkyl, cycloalkyl, phenyl, benzyl, alkylbenzene or unsaturated hydrocarbon group.

[0007] Preferably, the molar ratio between the alpha-diazo carbonyl compound, the amine compound, the base and the dichloromethane is (1-3):1:(0-3):150.

[0008] Preferably, the structural formula of the amine compound is shown as formula III to formula VII:

[0009]

[0010] wherein R 1 , R 2 is selected from one of alkyl, cycloalkyl, alkoxy, phenyl or benzyl.

[0011] Preferably, the structural formula of the alpha-diazo carbonyl compound is shown as formula IX:

[0012] Preferably, the structural formula of the alpha-diazo carbonyl compound is shown as formula IX:

[0013] wherein R 3 is selected from one of alkyl, cycloalkyl, phenyl, benzyl, alkylphenyl or unsaturated hydrocarbon group.

[0014] Preferably, the base is one of t-BuOK (potassium tert-butoxide), K3PO4, Cs2CO3, Et3N (triethylamine), DABCO (triethylene diamine), DBU (dicycloamidine), TMEDA (tetramethylethylenediamine), K2CO3, NaH2PO4, 2,6-dimethylpyridine, triethylamine trihydrofluoride, trimethoxy (trifluoromethyl) potassium borate or tetramethylmethane diamine.

[0015] Preferably, the heating reaction condition is 100℃ for 12h.

[0016] Preferably, in the column chromatography separation and purification, first, the silica gel column with 200-300 mesh is used for separation, and then the mixed solution of petroleum ether and ethyl acetate is used for elution, wherein the volume ratio of petroleum ether and ethyl acetate is 3:1-20:1.

[0017] Advantages of the present application

[0018] (1) The present application uses cheap and readily available amine compounds, α-diazo carbonyl compounds and dichloromethane as starting materials, dichloromethane as carbon source, and three-component coupling reaction occurs under the action of base, and β-amino-α-diazo derivative is constructed in one step.

[0019] (2) The method described in the present application has very wide substrate adaptability, does not need inert gas protection, does not need to use heavy metal, is easy to operate, avoids the use of noble metal, has low cost, and has less environmental pollution. DETAILED DESCRIPTION

[0020] The technical solutions of the present application are further illustrated by specific embodiments. However, the following examples are only simple examples of the present application, and do not represent or limit the protection scope of the present application, and the protection scope of the present application is subject to the claims.

[0021] Example 1

[0022] Synthesis of 2-diazo-3-(3,4-dihydroquinolin-1(2H)-yl)propionic acid ethyl ester (3aa)

[0023] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.45 mmol of diazoacetic acid ethyl ester (2a), 0.15 mmol of DABCO, sequentially, under air atmosphere, followed by reaction at 100 °C for 12 h to form a mixture product, the reaction product was concentrated by reduced pressure to obtain a crude product, the crude product was separated by silica gel (200 mesh) column extraction, using a mixture of petroleum ether and ethyl acetate (3:1~20:1) as eluent, the eluent was collected and dried to obtain 2-diazo-3-(3,4-dihydroquinolin-1(2H)-yl)propionic acid ethyl ester (3aa) 51.7 mg, yield 67%;

[0024]

[0025] The product had the following NMR data:

[0026] 1 H NMR (500 MHz, CDC13) δ 7.17-7.07 (m, 3H), 7.07-6.99 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.71 (s, 2H), 3.63 (s, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, CDC13) δ 167.10, 134.55, 134.13, 128.80, 126.72, 126.34, 125.80, 61.00, 54.86, 52.37, 49.91, 29.24, 14.63.

[0027] Example 2

[0028] Synthesis of 3-(azepan-1-yl)-2-diazo-propionic acid ethyl ester (3ba)

[0029] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.45 mmol of diazoacetic acid ethyl ester (2a), 0.15 mmol of DABCO, sequentially, under air atmosphere, followed by reaction at 100 °C for 12 h to form a mixture product, the reaction product was concentrated by reduced pressure to obtain a crude product, the crude product was separated by silica gel (200 mesh) column extraction, using a mixture of petroleum ether and ethyl acetate (3:1~20:1) as eluent, the eluent was collected and dried to obtain 2-diazo-3-(3,4-dihydroquinolin-1(2H)-yl)propionic acid ethyl ester (3aa) 51.7 mg, yield 67%;

[0030]

[0031] The NMR data of the product are as follows:

[0032] 1 H NMR (500 MHz, CDC13) δ 4.22 (q, J = 7.1 Hz, 2H), 3.58 (s, 2H), 2.70-2.66 (m, 4H), 1.58 (d, J = 2.8 Hz, 8H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, CDC13) δ 60.87, 54.87, 53.06, 29.86, 28.48, 27.08, 14.65.

[0033] Example 3

[0034] Synthesis of ethyl 2-diazo-3-(dipropylamino)propanoate (3da)

[0035] Under air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of diphenylamine (1c), 0.45 mmol of diazoacetic acid ethyl ester (2a), 0.45 mmol of Et3N were sequentially added into a 25 mL pressure tube, then the mixture was reacted at 100 °C for 12 hours to generate a product, the reaction product was concentrated by reduced pressure to obtain a crude product, the crude product was separated and extracted by silica gel (200 mesh) column, a mixture of petroleum ether and ethyl acetate (3:1 ~ 20:1) was used as eluent, the eluent was collected and dried to obtain 2-diazo-3-(dipropylamino)propanoic acid ethyl ester (3ca) 49.5 mg, with a yield of 51 %;

[0036]

[0037] The NMR data of the product are as follows:

[0038] 1 H NMR (500 MHz, CDC13) δ 4.22 (q, J = 7.1 Hz, 2H), 3.58 (s, 2H), 2.70-2.66 (m, 4H), 1.58 (d, J = 2.8 Hz, 8H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, CDC13) δ 60.87, 54.87, 53.06, 29.86, 28.48, 27.08, 14.65.

[0039] Example 4

[0040] Synthesis of ethyl 2-diazo-3-(dipropylamino)propanoate (3da)

[0041] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of diisopropylamine (1d), 0.6 mmol of diazoacetic acid ethyl ester (2a), 0.6 mmol of TMEDA, under air atmosphere, followed by reaction at 100 °C for 12 h to form a mixture product, the reaction product was concentrated by reduced pressure to obtain a crude product, the crude product was separated by silica gel (200 mesh) column extraction, using a mixture of petroleum ether and ethyl acetate (3:1 ~ 20:1) as eluent, the eluent was collected and dried to obtain 2-diazo-3-(dicyclohexylamino)propionic acid ethyl ester (3ea) 64.4 mg, yield 70%;

[0042]

[0043] The nuclear magnetic data of the product are as follows:

[0044] 1 H NMR (500 MHz, CDCI3) δ 4.22 (q, J = 7.1 Hz, 2H), 3.52 (s, 2H), 2.45-2.37 (t, 4H), 1.54-1.41 (m, 4H), 0.95-0.75 (t, 9H); 13 C NMR (126 MHz, CDCI3) δ 60.86, 55.62, 48.54, 29.86, 20.63, 14.65, 11.99.

[0045] Example 5

[0046] Synthesis of 2-diazo-3-(dicyclohexylamino)propionic acid ethyl ester (3ea)

[0047] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of diisopropylamine (1d), 0.6 mmol of diazoacetic acid ethyl ester (2a), 0.6 mmol of TMEDA, under air atmosphere, followed by reaction at 100 °C for 12 h to form a mixture product, the reaction product was concentrated by reduced pressure to obtain a crude product, the crude product was separated by silica gel (200 mesh) column extraction, using a mixture of petroleum ether and ethyl acetate (3:1 ~ 20:1) as eluent, the eluent was collected and dried to obtain 2-diazo-3-(dicyclohexylamino)propionic acid ethyl ester (3ea) 64.4 mg, yield 70%;

[0048]

[0049] The nuclear magnetic data of the product are as follows:

[0050] 1H NMR (500 MHz, CDC13) δ 4.22 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 2.56 (q, J = 7.1 Hz, 4H), 1.31 - 1.28 (t, 3H), 1.06 (t, J = 7.1 Hz, 6H); 13 C NMR (126 MHz, CDC13) δ 167.33, 60.54, 58.50, 40.59, 32.26, 26.56, 26.31, 14.71.

[0051] Example 6

[0052] Synthesis of 2-diazo-3-(diethylamino)propionic acid ethyl ester (3fa)

[0053] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of diethylamine (1f), 0.3 mmol of diazoacetic acid ethyl ester (2a), 0.45 mmol of Et3N, sequentially, under air atmosphere, and then the reaction was allowed to proceed for 12 hours at 100 °C to produce a mixture, which was concentrated by reduced pressure to produce a crude product, which was separated by column chromatography using silica gel (300 mesh), with a mixture of petroleum ether and ethyl acetate (3:1 ~ 20:1) as eluent, and the eluent was collected and dried to produce 2-diazo-3-(diethylamino)propionic acid ethyl ester (3fa) 36.5 mg, with a yield of 61%;

[0054]

[0055] The nuclear magnetic resonance data of the product are as follows:

[0056] 1 H NMR (500 MHz, CDC13) δ 4.22 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 2.56 (q, J = 7.1 Hz, 4H), 1.31 - 1.28 (t, 3H), 1.06 (t, J = 7.1 Hz, 6H); 13 C NMR (126 MHz, CDC13) δ 167.33, 60.54, 58.50, 40.59, 32.26, 26.56, 26.31, 14.71.

[0057] Example 7

[0058] Synthesis of 2-diazo-3-(piperidin-1-yl)propionic acid ethyl ester (3ga)

[0059] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of piperidine (1g), 0.9 mmol of diazoacetic acid ethyl ester (2a), 0.9 mmol of tetramethylmethane diamine, followed by reaction at 100 °C for 12 hours to form a mixture product, the reaction product was concentrated by reduced pressure to obtain a crude product, the crude product was separated by silica gel (200 mesh) column extraction, using a mixture of petroleum ether and ethyl acetate (3:1~20:1) as eluent, the eluent was collected and dried to obtain 2-diazo-3-(piperidin-1-yl)propionic acid ethyl ester (3ga) 41.5 mg, yield 54%;

[0060]

[0061] The nuclear magnetic data of the product are as follows:

[0062] 1 H NMR (500 MHz, CDCI3) δ 4.21 (q, J = 7.1 Hz, 2H), 3.43 (s, 2H), 2.49-2.37 (m, 4H), 1.62-1.53 (m, 4H), 1.47-1.36 (m, 2H), 1.29-1.25 (t, 3H); 13 C NMR (126 MHz, CDCI3) δ 167.28, 60.89, 53.37, 53.27, 26.02, 24.22, 14.61.

[0063] Example 8

[0064] Synthesis of 2-diazo-3-morpholino propionic acid ethyl ester (3ha)

[0065] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of piperidine (1g), 0.9 mmol of diazoacetic acid ethyl ester (2a), 0.9 mmol of tetramethylmethane diamine, followed by reaction at 100 °C for 12 hours to form a mixture product, the reaction product was concentrated by reduced pressure to obtain a crude product, the crude product was separated by silica gel (200 mesh) column extraction, using a mixture of petroleum ether and ethyl acetate (3:1~20:1) as eluent, the eluent was collected and dried to obtain 2-diazo-3-(piperidin-1-yl)propionic acid ethyl ester (3ga) 41.5 mg, yield 54%;

[0066]

[0067] The nuclear magnetic data of the product are as follows:

[0068] 1H NMR (500 MHz, CDCI3) δ 4.22 (q, J = 7.1 Hz, 2H), 3.46 (s, 2H), 2.39-2.32 (m, 2H), 2.25 (s, 3H), 1.56-1.43 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H); 13 C NMR (126 MHz, CDCI3) δ 167.25, 60.92, 58.35, 51.92, 41.53, 20.69, 14.63, 11.93.

[0069] Example 9

[0070] Synthesis of ethyl 2-diazo-3-(methyl(propyl)amino)propanoate (3ia)

[0071] To a 25 mL pressure tube was added 45 mmol of ethyl 2-diazoacetate (3a), 0.3 mmol of N-methylpropylamine (1i), 0.45 mmol of ethyl diazoacetate (2a), 0.45 mmol of K2CO3, successively, under air atmosphere, and then the reaction was carried out at 100 °C for 12 hours to give a mixture product, which was concentrated by reduced pressure to give a crude product, which was separated by column chromatography on silica gel (200 mesh) using a mixture of petroleum ether and ethyl acetate (3:1 ~ 20:1) as an eluent, and the eluent was collected and dried to give ethyl 2-diazo-3-(methyl(propyl)amino)propanoate (3ia) 35.8 mg, in a yield of 60%;

[0072]

[0073] The NMR data of the product are as follows:

[0074] 1 H NMR (500 MHz, CDCI3) δ 4.22 (q, J = 7.1 Hz, 2H), 3.46 (s, 2H), 2.39-2.32 (m, 2H), 2.25 (s, 3H), 1.56-1.43 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H); 13 C NMR (126 MHz, CDCI3) δ 167.25, 60.92, 58.35, 51.92, 41.53, 20.69, 14.63, 11.93.

[0075] Example 10

[0076] Synthesis of butyl 2-diazo-3-(3,4-dihydroisoquinolin-2(lH)-yl)propanoate (3ab)

[0077] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.3 mmol of 2-diazonium butyl acetate (2b), 0.45 mmol of NaH2PO4, successively under air atmosphere, and then the reaction was carried out at 100°C for 12 hours to produce a mixture, which was concentrated by reduced pressure to obtain a crude product, which was separated by silica gel (300 mesh) column extraction using a mixture of petroleum ether and ethyl acetate (3:1~20:1) as an eluent, and the eluent was collected and dried to obtain 2-diazonium-3-(3,4-dihydroisoquinoline-2(lH)-yl)propionic acid butyl ester (3ab) 48.4 mg, with a yield of 56%;

[0078]

[0079] The nuclear magnetic resonance data of the product are as follows:

[0080] 1 H NMR (500 MHz, CDCl3) δ 7.15-7.08 (m, 3H), 7.05-7.01 (m, 1H), 4.21 (t, J = 6.7 Hz, 2H), 3.71 (s, 2H), 3.63 (s, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 1.65 (dt, J = 14.5, 6.7 Hz, 2H), 1.47-1.33 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13 CNMR (126 MHz, CDCl3) δ 167.19, 134.56, 134.15, 128.82, 126.74, 126.37, 125.83, 64.93, 54.88, 52.41, 49.94, 31.10, 29.25, 19.26, 13.80.

[0081] Example 11

[0082] Synthesis of phenethyl 2-diazonium-3-(3,4-dihydroisoquinoline-2(lH)-yl)propionate (3ac)

[0083] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (la), 0.6 mmol of phenethyl diazoacetate (2c), 0.45 mmol of triethylamine trihydrofluoride, sequentially, under air atmosphere, and then reacted at 100°C for 12 hours to form a mixture product, which was concentrated by reduced pressure to obtain a crude product. The crude product was separated by column chromatography using silica gel (200 mesh) and a mixture of petroleum ether and ethyl acetate (3:1-20:1) as an eluent. The eluent was collected and dried to obtain 60.3 mg of phenethyl 2-diazo-3-(3,4-dihydroisoquinolin-2(lH)-yl)propanoate (3ac) with a yield of 60%;

[0084]

[0085] The nuclear magnetic resonance data of the product are as follows:

[0086] 1 HNMR (500 MHz, CDC13) δ 7.35-7.29 (m, 2H), 7.28-7.21 (m, 3H), 7.17-7.07

[0087] (m, 3H), 7.02 (d, J = 6.1 Hz, 1H), 4.42 (t, J = 6.9 Hz, 2H), 3.67 (s, 2H), 3.60 (s, 2H), 2.98 (t, J = 6.9 Hz, 2H), 2.90 (t, J = 5.8 Hz, 2H), 2.77 (t, J = 5.5 Hz, 2H); 13 CNMR (126 MHz, CDC13) δ 166.99, 137.91, 134.54, 134.14, 129.09, 128.81, 128.65, 126.75, 126.74, 126.59, 126.37, 65.45, 54.86, 52.34, 49.90, 35.60, 29.25.

[0088] Example 12

[0089] Synthesis of 2-phenylpropyl 2-diazo-3-(3,4-dihydroisoquinolin-2(lH)-yl)propanoate (3ad)

[0090] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.3 mmol of 2-phenylpropyl 2-diazoacetate (2d), 0.6 mmol of 2,6-lutidine, and then reacted at 100°C for 12 hours under an air atmosphere to produce a mixture, which was concentrated by reduced pressure to produce a crude product. The crude product was separated by column chromatography using silica gel (300 mesh) and a mixture of petroleum ether and ethyl acetate (3:1-20:1) as an eluent. The eluent was collected and dried to produce 2-phenylpropyl 2-diazo-3-(3,4-dihydroisoquinolin-2(lH)-yl)propanoate (3ad) 56.4 mg at a yield of 54%.

[0091]

[0092] The nuclear magnetic resonance data of the product are as follows:

[0093] 1 H NMR (500 MHz, CDC13) δ 7.36 - 7.29 (m, 2H), 7.28 - 7.21 (m, 3H), 7.18 - 7.08 (m, 3H), 7.02 (d, J = 6.0 Hz, 1H), 4.29 (ddd, J = 25.4, 10.6, 7.1 Hz, 2H), 3.65 (s, 2H), 3.57 (s, 2H), 3.25 - 3.08 (m, 1H), 2.89 (t, J = 5.5 Hz, 2H), 2.74 (s, 2H), 1.33 (t, J = 6.8 Hz, 3H); 13 C NMR (126 MHz, CDC13) δ 166.97, 143.19, 134.52, 134.12, 128.80, 128.62, 127.46, 126.86, 126.74, 126.36, 125.80, 69.87, 54.81, 52.31, 49.85, 39.37, 29.24, 17.90.

[0094] Example 13

[0095] Synthesis of cyclohexyl 2-diazo-3-(3,4-dihydroisoquinolin-2(lH)-yl)propanoate (3ae)

[0096] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.45 mmol of cyclohexyl 2-diazoacetate (2e), no base, then 100 °C for 12 hours to form a mixture, the reaction product was concentrated by reduced pressure to obtain a crude product, the crude product was separated by silica gel (200 mesh) column extraction, using a mixture of petroleum ether and ethyl acetate (3:1-20:1) as eluent, collecting the eluent and drying to obtain cyclohexyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanoate (3ae) 45.1 mg, yield 48%;

[0097]

[0098] The product had the following NMR data:

[0099] 1 H NMR (500 MHz, CDCl3) δ 7.16-7.08 (m, 3H), 7.06-7.01 (m, 1H), 4.96-4.84 (m, 1H), 3.71 (s, 2H), 3.63 (s, 2H), 2.91 (t, J = 5.8 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 1.87 (dd, J = 12.4, 4.9 Hz, 2H), 1.80-1.67 (m, 2H), 1.60-1.33 (m, 6H); 13 C NMR (126 MHz, CDCl3) δ 166.68, 134.61, 134.16, 128.81, 126.74, 126.34, 125.80, 73.29, 54.86, 52.45, 49.92, 31.97, 29.29, 25.57, 23.74.

[0100] Example 14

[0101] Synthesis of 2-methylallyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanoate (3af)

[0102] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.6 mmol of 2-methylallyl 2-diazoacetate (2f), 0.45 mmol of K3PO4, successively under air atmosphere, and then the reaction was carried out at 100°C for 12 hours to produce a mixture, which was concentrated by reduced pressure to obtain a crude product. The crude product was separated by column chromatography using silica gel (300 mesh) and a mixture of petroleum ether and ethyl acetate (3:1-20:1) as an eluent. The eluent was collected and dried to obtain 2-methylallyl 2-diazo-3-(3,4-dihydroisoquinolin-2(lH)-yl)propanoate (3af) 37.8 mg, with a yield of 42%.

[0103]

[0104] The nuclear magnetic resonance data of the product are as follows:

[0105] 1 H NMR (500 MHz, CDCI3) δ 7.18-7.08 (m, 3H), 7.06-7.01 (m, 1H), 4.99 (s, 1H), 4.95 (s, 1H), 4.63 (s, 2H), 3.71 (s, 2H), 3.64 (s, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.9 Hz, 2H), 1.78 (s, 3H); 13 C NMR (126 MHz, CDCI3) δ 166.73, 140.14, 134.52, 134.13, 128.81, 126.73, 126.37, 125.82, 112.90, 68.09, 54.89, 52.39, 49.95, 29.26, 19.51.

[0106] Example 15

[0107] Synthesis of pentan-3-yl 2-diazo-3-(3,4-dihydroisoquinolin-2(lH)-yl)propanoate (3ag)

[0108] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.3 mmol of pentan-3-yl 2-diazoacetate (2g), 0.9 mmol of TMEDA, sequentially, under air atmosphere, and then the reaction was allowed to proceed at 100 °C for 12 hours to form a mixture of products, which was concentrated by reduced pressure to obtain a crude product, which was separated by column chromatography on silica gel (200 mesh) using a mixture of petroleum ether and ethyl acetate (3:1 to 20:1) as eluent, and the eluent was collected and dried to obtain pentan-3-yl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanoate (3ag) 43.3 mg in a yield of 48%.

[0109]

[0110] The NMR data of the product are as follows:

[0111] 1 H NMR (500 MHz, CDCl3) δ 7.17-7.08 (m, 3H), 7.07-7.00 (m, 1H), 5.03-4.74 (m, 1H), 3.71 (s, 2H), 3.65 (s, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 1.68-1.55 (m, 4H), 0.92 (t, J = 7.5 Hz, 6H); 13 C NMR (126 MHz, CDCl3) δ 167.11, 134.60, 134.14, 128.79, 126.71, 126.33, 125.79, 54.82, 52.44, 49.90, 29.28, 26.74, 9.63.

[0112] Example 16

[0113] Synthesis of isopropyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanoate (3ah)

[0114] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.45 mmol of 2-diazonium isopropyl acetate (2h), 0.9 mmol of t-BuOK, successively under air atmosphere, and then the reaction was carried out at 100°C for 12 hours to produce a mixture, which was concentrated by reduced pressure to obtain a crude product. The crude product was separated by column chromatography using silica gel (200 mesh) and a mixture of petroleum ether and ethyl acetate (3:1-20:1) as an eluent. The eluent was collected and dried to obtain 2-diazonium-3-(3,4-dihydroisoquinolin-2(1H)-yl)propionic acid isopropyl ester (3ah) 40.5 mg, with a yield of 50%.

[0115]

[0116] The nuclear magnetic resonance data of the product are as follows:

[0117] 1 H NMR (500 MHz, CDCl3) δ 7.11 (dtd, J = 8.6, 5.8, 2.6 Hz, 3H), 7.06-7.01 (m, 1H), 5.12 (dt, J = 12.5, 6.3 Hz, 1H), 3.71 (s, 2H), 3.63 (s, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 1.28 (t, J = 7.7 Hz, 6H); 13 C NMR (126 MHz, CDCl3) δ 166.74, 134.60, 134.16, 128.81, 126.74, 126.35, 125.81, 68.58, 54.85, 52.41, 49.91, 29.27, 22.22.

[0118] Example 17

[0119] Synthesis of 3-phenylprop-2-yn-1-yl 2-diazonium-3-(3,4-dihydroisoquinolin-2(1H)-yl)propionate (3ai)

[0120] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.45 mmol of 3-phenylprop-2-yn-1-yl 2-diazoacetate (2i), 0.45 mmol of Cs2CO3, and then reacted at 100°C for 12 hours under an air atmosphere to produce a mixture, which was concentrated by reduced pressure to produce a crude product. The crude product was separated by column chromatography using silica gel (200 mesh) and a mixture of petroleum ether and ethyl acetate (3:1 to 20:1) as an eluent. The eluent was collected and dried to produce 3-phenylprop-2-yn-1-yl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanoate (3ai) 44.8 mg, with a yield of 42%.

[0121]

[0122] The nuclear magnetic resonance data of the product are as follows:

[0123] 1 H NMR (500 MHz, CDC13) δ 7.53-7.43 (m, 2H), 7.41-7.29 (m, 3H), 7.19-7.08 (m, 3H), 7.06-6.99 (m, 1H), 5.05 (s, 2H), 3.73 (s, 2H), 3.66 (s, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.83 (t, J = 5.9 Hz, 2H); 13 C NMR (126 MHz, CDC13) δ 166.30, 134.44, 134.07, 132.04, 128.88, 128.79, 128.42, 126.73, 126.36, 125.80, 122.33, 86.73, 83.26, 54.84, 53.20, 52.35, 49.90, 29.20.

[0124] Example 18

[0125] Synthesis of 1-phenylprop-2-yl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanoate (3aj)

[0126] To a 25 mL pressure tube was added 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.6 mmol of 1-phenylpropan-2-yl 2-diazoacetate (2j), 0.15 mmol of DBU, sequentially, under air atmosphere, and then the reaction was allowed to proceed at 100 °C for 12 h to yield a mixture of products. The reaction product was concentrated by reduced pressure to yield a crude product, which was separated by column chromatography on silica gel (200 mesh) using a mixture of petroleum ether and ethyl acetate (3:1 to 20:1) as eluent. The eluent was collected and dried to yield 1-phenylpropan-2-yl 2-diazo-3-(3,4-dihydroisoquinolin-2(lH)-yl)propanoate (3aj) 45.1 mg in 41% yield.

[0127]

[0128] The NMR data of the product are as follows:

[0129] 1 H NMR (500 MHz, CDC13) δ 7.33 - 7.27 (m, 2H), 7.22 (dd, J = 7.3, 3.0 Hz, 3H), 7.18 - 7.09 (m, 3H), 7.05 - 7.00 (m, 1H), 5.30 - 5.18 (m, 1H), 3.65 (s, 2H), 3.58 (s, 2H), 3.04 - 2.66 (m, 6H), 1.30 (t, J = 6.8 Hz, 3H); 13 C NMR (126 MHz, CDC13) δ 166.57, 137.59, 134.52, 134.09, 129.58, 128.77, 128.45, 126.72, 126.62, 126.32, 125.76, 72.23, 54.75, 52.27, 49.77, 42.63, 29.22, 19.94.

Claims

1. A method for preparing a β-amino-α-diazo derivative, characterized in that: An α-diazo carbonyl compound, an amine compound, a base, and dichloromethane are added to a reactor and heated to react in an air atmosphere. The reaction product is concentrated, separated and purified by column chromatography, and then dried to obtain a β-amino-α-diazo derivative. The structural formula of the β-amino-α-diazo derivative is shown in Formula I or Formula II: The structural formulas of the amine compounds are shown in Formula III to Formula VII: The structural formula of the α-diazocarbonyl compound is shown in Formula IX: Where: R 1 、R 2 is selected from one of alkyl, cycloalkyl or benzyl; R 3 One selected from alkyl, cycloalkyl, phenyl, benzyl, alkylbenzene or unsaturated hydrocarbon groups.

2. The method for preparing the β-amino-α-diazo derivative according to claim 1, wherein: The molar ratio of the α-diazocarbonyl compound, the amine compound, the base and the dichloromethane is (1-3):1:(0-3):

150.

3. The method for preparing the β-amino-α-diazo derivative according to claim 1, wherein: The base is one of t-BuOK, K3PO4, Cs2CO3, Et3N, DABCO, DBU, TMEDA, K2CO3, NaH2PO4, 2,6-lutidine, triethylamine trihydrofluoride, potassium trimethoxy(trifluoromethyl)borate or tetramethylmethanediamine.

4. The method for preparing the β-amino-α-diazo derivative according to claim 1, wherein: The heating reaction conditions were 100°C for 12 h.

5. The method for preparing the β-amino-α-diazo derivative according to claim 1, wherein: In the column chromatography separation and purification, first use a 200-300 mesh silica gel column for separation, and then use a mixture of petroleum ether and ethyl acetate for elution, wherein the volume ratio of petroleum ether to ethyl acetate is 3:1-20:1.

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