Preparation method of beta-amino-alpha-diazo derivative

Abstract

The invention discloses a preparation method of a beta-amino-alpha-diazo derivative, and belongs to the technical field of medical intermediates and organic synthesis. The method comprises the following steps: taking an alpha-diazocarbonyl compound and an amine compound as raw materials, taking dichloromethane as a carbon source, and carrying out a three-component coupling reaction in an air atmosphere under the action of alkali to generate a beta-amino-alpha-diazo derivative; the method disclosed by the invention has the advantages of very wide substrate adaptability, cheap and easily available initial raw materials of the reaction, simple and convenient operation in the reaction process, suitability for large-scale synthesis and capability of providing a new method and a new target for synthesis and modification of medicines.

Description

Technical Field

[0001] The invention relates to a method for preparing a beta-amino-alpha-diazo derivative, and belongs to the technical field of pharmaceutical intermediates and organic synthesis. Background Art

[0002] Diazo compounds, as an important class of organic compounds, can undergo a variety of chemical transformations and are widely used in the fields of drug development, new material creation, etc. Natural diazo compounds have intrinsic anti-tumor and antibacterial activities and have potential clinical application value. For example, Lomaiviticin A has antitumor activity at submicromolar concentrations (He, H., Ding, W.-D., Bernan, VS, Richardson, AD, Ireland, CM, Greenstein, M., Ellestad, GA, and Carter, GT (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,SA,Haskell,TH,Frohardt,RP,and Bartz,QR(1954)Azaserine,a new tumor-inhibitory substance.Structural studies.J.Am.Chem.Soc.76,2881-2883); 6-diazo-5-oxonorleucine (DON) has beneficial activity against various cancers, lymphomas and Hodgkin's disease (Rahman,A.,Smith,FP,Luc,P.-V.,andWoolley,PV(1985)Phase I study and clinical pharmacology of6-diazo-5-oxo-L-norleucine(DON).Invest.New Drugs 3,369-374.), etc.

[0003] Diazo compounds are also a kind of multifunctional intermediates in organic synthetic chemistry, but there are few diazo compounds that can be directly obtained in nature. At present, although the synthesis method of diazo compounds has been greatly developed, there are defects such as complicated operation, harsh reaction conditions, difficult to obtain raw materials, and environmental pollution and troublesome post-treatment of heavy metal catalysts used. Therefore, it is necessary to develop a safe, efficient, clean, easy to operate, and low-cost method for synthesizing diazo compounds. In the reported three-component reaction, an imine generated by the reaction of an amine and an aldehyde is usually coupled with a nucleophilic reagent to generate a target product. Based on this, the present invention uses a cheap and readily available dichloromethane compound and an amine to first couple through C-halogen and NH activation, and the generated imine is then reacted with a nucleophilic reagent α-diazo carbonyl compound, thereby smoothly obtaining a β-amino-α-diazo derivative. Summary of the invention

[0004] In view of the shortcomings of the above-mentioned prior art, the present invention has developed a new method for preparing β-amino-α-diazo derivatives with the advantages of simple and easy-to-obtain raw materials, no need for inert gas protection, simple operation, avoidance of the use of precious metals, and low cost. The specific steps are: adding an α-diazo carbonyl compound, an amine compound, a base, and dichloromethane to a reactor, heating and reacting in an air atmosphere, concentrating the reaction product, separating and purifying it by column chromatography, and drying it to obtain a β-amino-α-diazo derivative. The structural formula of the β-amino-α-diazo derivative is shown in Formula I and Formula II:

[0005]

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

[0007] Preferably, the molar ratio of the α-diazocarbonyl compound, the amine compound, the base and dichloromethane is (1-3):1:(0-3):150.

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

[0009]

[0010] Where R 1 , R 2 One selected from alkyl, cycloalkyl, alkoxy, phenyl or benzyl.

[0011] Preferably, the structural formula of the α-diazocarbonyl compound is as shown in Formula IX:

[0012]

[0013] Among them, R 3 It is selected from one of an alkyl group, a cycloalkyl group, a phenyl group, a benzyl group, an alkylbenzene group or an unsaturated hydrocarbon group.

[0014] Preferably, the base is one of t-BuOK (potassium tert-butoxide), K3PO4, Cs2CO3, Et3N (triethylamine), DABCO (triethylenediamine), DBU (dicyclic amidine), TMEDA (tetramethylethylenediamine), K2CO3, NaH2PO4, 2,6-lutidine, triethylamine trihydrofluoride, potassium trimethoxy(trifluoromethyl)borate or tetramethylmethanediamine.

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

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

[0017] Beneficial Effects of the Invention

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

[0019] (2) The method of the present invention has a very wide substrate adaptability, does not require inert gas protection, does not require the use of heavy metals, is easy to operate, avoids the use of precious metals, is low in cost, and has little pollution to the environment. DETAILED DESCRIPTION

[0020] The technical solution of the present invention is further described below by specific implementation methods. However, the following embodiments are only simple examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0021] Example 1

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

[0023] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.45 mmol of ethyl diazoacetate (2a), and 0.15 mmol of DABCO were added to a 25 mL pressure tube in sequence, and then reacted at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 51.7 mg of ethyl 2-diazo-3-(3,4-dihydroquinolin-1(2H)-yl)propanoate (3aa), with a yield of 67%;

[0024]

[0025] The NMR data of the product are as follows:

[0026] 1 H NMR (500MHz, CDCl3) δ7.17-7.07(m,3H),7.07-6.99(m,1H),4.26(q,J=7.1Hz,2H),3.71( s,2H),3.63(s,2H),2.92(t,J=5.8Hz,2H),2.81(t,J=5.9Hz,2H),1.30(t,J=7.1Hz,3H); 13 C NMR (126MHz, CDCl3) δ167.10,134.55,134.13,128.80,126.72,126.34,125.80,61.00,54.86,52.37,49.91,29.24,14.63.

[0027] Example 2

[0028] Synthesis of ethyl 3-(aza-1-yl)-2-diazopropionate (3ba)

[0029] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of cycloheximide (1b), 0.36 mmol of ethyl diazoacetate (2a), and 0.3 mmol of Et3N were added to a 25 mL pressure tube in sequence, and then reacted at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 39.2 mg of ethyl 3-(aza-1-yl)-2-diazopropionate (3ba), with a yield of 58%;

[0030]

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

[0032] 1 H NMR (500MHz, CDCl3) δ4.22 (q, J = 7.1Hz, 2H), 3.58 (s, 2H), 2.70-2.66 (m, 4H), 1.58 (d, J = 2.8Hz, 8H), 1.28 (t, J = 7.1Hz, 3H); 13 C NMR (126MHz, CDCl3) δ60.87,54.87,53.06,29.86,28.48,27.08,14.65.

[0033] Example 3

[0034] Synthesis of ethyl 2-diazo-3-(dibenzylamino)propionate (3ca)

[0035] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of dibenzylamine (1c), 0.45 mmol of ethyl diazoacetate (2a), and 0.45 mmol of Et3N were added to a 25 mL pressure tube in sequence, and then reacted at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 49.5 mg of ethyl 2-diazo-3-(dibenzylamino)propionate (3ca), with a yield of 51%;

[0036]

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

[0038] 1 H NMR(500MHz, CDCl3)δ7.36(d,J=7.2Hz,4H),7.35-7.29(m,4H),7.24(d,J=7.2H z,2H),4.20(q,J=7.1Hz,2H),3.65(s,4H),3.50(s,2H),1.26(t,J=7.1Hz,3H); 13 CNMR (126MHz, CDCl3) δ167.12,139.18,128.80,128.47,127.26,60.89,57.92,48.04,14.64.

[0039] Example 4

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

[0041] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of dipropylamine (1d), 0.6 mmol of ethyl diazoacetate (2a), and 0.6 mmol of TMEDA were added to a 25 mL pressure tube in sequence, and then reacted at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 47.1 mg of ethyl 2-diazo-3-(dipropylamino)propionate (3da), with a yield of 69%;

[0042]

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

[0044] 1 H NMR (500MHz, CDCl3) δ4.22 (q, J = 7.1Hz, 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 (126MHz, CDCl3) δ60.86,55.62,48.54,29.86,20.63,14.65,11.99.

[0045] Example 5

[0046] Synthesis of ethyl 2-diazo-3-(dicyclohexylamino)propionate (3ea)

[0047] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of dicyclohexylamine (1e), 0.75 mmol of ethyl diazoacetate (2a), and 0.75 mmol of DBU were added to a 25 mL pressure tube in sequence, and then reacted at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 64.4 mg of ethyl 2-diazo-3-(dicyclohexylamino)propionate (3ea), with a yield of 70%;

[0048]

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

[0050] 1H NMR (500MHz, CDCl3) δ4.21 (q, J = 7.1Hz, 2H), 3.54 (s, 2H), 1.77-1.66 (m, 8H), 1.63-1.55 (m, 2H), 1.32-1.16 (m, 12H), 1.10-1.00 (t, 3H); 13 C NMR (126MHz, CDCl3) δ167.33,60.54,58.50,40.59,32.26,26.56,26.31,14.71.

[0051] Example 6

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

[0053] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of diethylamine (1f), 0.3 mmol of ethyl diazoacetate (2a), and 0.45 mmol of Et3N were added to a 25 mL pressure tube in sequence, and then reacted at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (300 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 36.5 mg of ethyl 2-diazo-3-(diethylamino)propionate (3fa), with a yield of 61%;

[0054]

[0055] The NMR data of the product are as follows:

[0056] 1 H NMR (500MHz, CDCl3) δ4.22(q,J=7.1Hz,2H),3.56(s,2H),2.56(q,J=7.1Hz,4H),1.31-1.28(t,3H),1.06(t,J=7.1Hz,6H); 13 C NMR (126MHz, CDCl3) δ167.41,60.88,47.46,46.77,14.63,12.29.

[0057] Example 7

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

[0059] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of piperidine (1 g), 0.9 mmol of ethyl diazoacetate (2a), and 0.9 mmol of tetramethylmethanediamine were added to a 25 mL pressure tube in sequence, and then reacted at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 41.5 mg of ethyl 2-diazo-3-(piperidin-1-yl)propionate (3ga), with a yield of 54%;

[0060]

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

[0062] 1 H NMR (500MHz, CDCl3) δ4.21 (q, J = 7.1Hz, 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 (126MHz, CDCl3) δ167.28,60.89,53.37,53.27,26.02,24.22,14.61.

[0063] Example 8

[0064] Synthesis of ethyl 2-diazo-3-morpholinopropionate (3HA)

[0065] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of morpholine (1h), 0.3 mmol of ethyl diazoacetate (2a), and 0.6 mmol of potassium trimethoxy(trifluoromethyl)borate were added to a 25 mL pressure tube in sequence, and then reacted at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 28.1 mg of ethyl 2-diazo-3-morpholinopropionate (3ha), with a yield of 42%;

[0066]

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

[0068] 1H NMR (500MHz, CDCl3) δ4.21 (q, J = 7.1Hz, 2H), 3.43 (s, 2H), 2.46-2.41 (m, 2H), 1. 57(dt,J=11.1,5.6Hz,4H),1.41(dt,J=7.2,5.8Hz,2H),1.27(t,J=7.1Hz,3H); 13 C NMR (126MHz, CDCl3) δ170.19,66.97,61.02,53.48,52.54,14.61.

[0069] Example 9

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

[0071] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of N-methylpropylamine (1i), 0.45 mmol of ethyl diazoacetate (2a), and 0.45 mmol of K2CO3 were added to a 25 mL pressure tube in sequence, and then reacted at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 35.8 mg of ethyl 2-diazo-3-(methyl(propyl)amino)propionate (3ia), with a yield of 60%;

[0072]

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

[0074] 1 H NMR (500MHz, CDCl3) δ4.22 (q, J = 7.1Hz, 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=7.1Hz,3H),0.89(t,J=7.4Hz,3H); 13 C NMR (126MHz, CDCl3) δ167.25,60.92,58.35,51.92,41.53,20.69,14.63,11.93.

[0075] Example 10

[0076] Synthesis of 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propionic acid butyl ester (3ab)

[0077] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.3 mmol of 2-diazoacetic acid butyl ester (2b), and 0.45 mmol of NaH2PO4 were added to a 25 mL pressure tube in sequence, and then reacted at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (300 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 48.4 mg of 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propionic acid butyl ester (3ab), with a yield of 56%;

[0078]

[0079] The NMR data of the product are as follows:

[0080] 1 H NMR (500MHz, CDCl3) δ7.15-7.08(m,3H),7.05-7.01(m,1H),4.21(t,J=6.7Hz,2H),3.71(s,2H),3.63(s,2H),2.9 1(t,J=5.9Hz,2H),2.81(t,J=5.9Hz,2H),1.65(dt,J=14.5,6.7Hz,2H),1.47-1.33(m,2H),0.95(t,J=7.4Hz,3H); 13 CNMR (126MHz, CDCl3) δ167.19,134.56,134.15,128.82,126.74,126.37,125.83,64.93,54.88,52.41,49.94,31.10,29.25,19.26,13.80.

[0081] Embodiment 11

[0082] Synthesis of Phenethyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propionate (3ac)

[0083] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.6 mmol of phenethyl diazoacetate (2c), and 0.45 mmol of triethylamine trihydrofluoride were added to a 25 mL pressure tube in sequence, and then reacted at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1 to 20:1) was used as an eluent. The eluent was collected and dried to obtain 60.3 mg of phenethyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl) propionate (3ac), with a yield of 60%;

[0084]

[0085] The NMR data of the product are as follows:

[0086] 1 HNMR(500MHz, CDCl3)δ7.35-7.29(m,2H),7.28-7.21(m,3H),7.17-7.07

[0087] (m,3H),7.02(d,J=6.1Hz,1H),4.42(t,J=6.9Hz,2H),3.67(s,2H),3.60(s ,2H),2.98(t,J=6.9Hz,2H),2.90(t,J=5.8Hz,2H),2.77(t,J=5.5Hz,2H); 13 CNMR (126MHz, CDCl3) δ166.99,137.91,134.54,134.14,129.09,128.81,128.6 5,126.75,126.74,126.59,126.37,65.45,54.86,52.34,49.90,35.60,29.25.

[0088] Example 12

[0089] Synthesis of 2-phenylpropyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl) propionate (3ad)

[0090] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.3 mmol of 2-phenylpropyl 2-diazoacetate (2d), and 0.6 mmol of 2,6-lutidine were added to a 25 mL pressure tube in sequence, and then reacted at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (300 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 56.4 mg of 2-phenylpropyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl) propionate (3ad), with a yield of 54%;

[0091]

[0092] The NMR data of the product are as follows:

[0093] 1 H NMR (500MHz, CDCl3) δ7.36-7.29(m,2H),7.28-7.21(m,3H),7.18-7.08(m,3H),7.02(d,J=6.0Hz,1H),4.29(ddd,J=25.4, 10.6,7.1Hz,2H),3.65(s,2H),3.57(s,2H),3.25-3.08(m,1H),2.89(t,J=5.5Hz,2H),2.74(s,2H),1.33(t,J=6.8Hz,3H); 13 C NMR (126MHz, CDCl3) δ166.97,143.19,134.52,134.12,128.80,128.62,127.46,1 26.86,126.74,126.36,125.80,69.87,54.81,52.31,49.85,39.37,29.24,17.90.

[0094] Embodiment 13

[0095] Synthesis of Cyclohexyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl) Propionate (3ae)

[0096] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), and 0.45 mmol of cyclohexyl 2-diazoacetate (2e) were added to a 25 mL pressure tube in sequence without adding a base, and then reacted at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (200 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1 to 20:1) was used as an eluent. The eluent was collected and dried to obtain 45.1 mg of cyclohexyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl) propionate (3ae), with a yield of 48%;

[0097]

[0098] The NMR data of the product are as follows:

[0099] 1 H NMR (500MHz, CDCl3) δ7.16-7.08(m,3H),7.06-7.01(m,1H),4.96-4.84(m,1H),3.71(s,2H),3.63(s,2H),2.9 1(t,J=5.8Hz,2H),2.81(t,J=5.9Hz,2H),1.87(dd,J=12.4,4.9Hz,2H),1.80–1.67(m,2H),1.60–1.33(m,6H); 13 C NMR (126MHz, CDCl3) δ166.68,134.61,134.16,128.81,126.74,126.34,125.80,73.29,54.86,52.45,49.92,31.97,29.29,25.57,23.74.

[0100] Embodiment 14

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

[0102] In an air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.6 mmol of 2-methylallyl 2-diazoacetate (2f), and 0.45 mmol of K3PO4 were added to a 25 mL pressure tube in sequence, and then reacted at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted by a silica gel (300 mesh) column, and a mixed solution of petroleum ether and ethyl acetate (3:1-20:1) was used as an eluent. The eluent was collected and dried to obtain 37.8 mg of 2-methylallyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl) propionate (3af), with a yield of 42%;

[0103]

[0104] The NMR data of the product are as follows:

[0105] 1 H NMR (500MHz, CDCl3) δ7.18-7.08(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=5.8Hz,2H),2.82(t,J=5.9Hz,2H),1.78(s,3H); 13 C NMR (126MHz, CDCl3) δ166.73,140.14,134.52,134.13,128.81,126.73,126.37,125.82,112.90,68.09,54.89,52.39,49.95,29.26,19.51.

[0106] Embodiment 15

[0107] Synthesis of Pentan-3-yl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanoate (3ag)

[0108] Under air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.3 mmol of pentane-3-yl 2-diazoacetate (2 g) and 0.9 mmol of TMEDA were added to a 25 mL pressure tube in sequence, followed by reaction at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted on a silica gel (200 mesh) column using a mixed solution of petroleum ether and ethyl acetate (3:1 to 20:1) as an eluent. The eluent was collected and dried to obtain 43.3 mg of pentane-3-yl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl) propionate (3ag), with a yield of 48%.

[0109]

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

[0111] 1 H NMR (500MHz, CDCl3) δ7.17-7.08(m,3H),7.07-7.00(m,1H),5.03-4.74(m,1H),3.71(s,2H),3.6 5(s,2H),2.92(t,J=5.8Hz,2H),2.81(t,J=5.9Hz,2H),1.68-1.55(m,4H),0.92(t,J=7.5Hz,6H); 13 C NMR (126MHz, CDCl3) δ167.11,134.60,134.14,128.79,126.71,126.33,125.79,54.82,52.44,49.90,29.28,26.74,9.63.

[0112] Example 16

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

[0114] Under air atmosphere, 45 mmol of dichloromethane (3a), 0.3 mmol of 1,2,3,4-tetrahydroisoquinoline (1a), 0.45 mmol of isopropyl 2-diazoacetate (2h) and 0.9 mmol of t-BuOK were added to a 25 mL pressure tube in sequence, followed by reaction at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted on a silica gel (200 mesh) column using a mixed solution of petroleum ether and ethyl acetate (3:1 to 20:1) as an eluent. The eluent was collected and dried to obtain 40.5 mg of isopropyl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl)propanoate (3ah), with a yield of 50%.

[0115]

[0116] The NMR data of the product are as follows:

[0117] 1 H NMR(500MHz, CDCl3)δ7.11(dtd,J=8.6,5.8,2.6Hz,3H),7.06-7.01(m,1H),5.12(dt,J=12.5,6.3Hz ,1H),3.71(s,2H),3.63(s,2H),2.92(t,J=5.8Hz,2H),2.81(t,J=5.9Hz,2H),1.28(t,J=7.7Hz,6H); 13 C NMR (126MHz, CDCl3) δ166.74,134.60,134.16,128.81,126.74,126.35,125.81,68.58,54.85,52.41,49.91,29.27,22.22.

[0118] Embodiment 17

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

[0120] Under air atmosphere, 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) and 0.45 mmol of Cs2CO3 were added to a 25 mL pressure tube in sequence, followed by reaction at 100°C for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product, which was separated and extracted on a silica gel (200 mesh) column using a mixed solution of petroleum ether and ethyl acetate (3:1 to 20:1) as an eluent. The eluent was collected and dried to obtain 44.8 mg of 3-phenylprop-2-yn-1-yl 2-diazo-3-(3,4-dihydroisoquinoline-2(1H)-yl) propanoate (3ai), with a yield of 42%.

[0121]

[0122] The NMR data of the product are as follows:

[0123] 1 H NMR (500MHz, CDCl3) δ7.53-7.43(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=5.8Hz,2H),2.83(t,J=5.9Hz,2H); 13 C NMR (126MHz, CDCl3) δ166.30,134.44,134.07,132.04,128.88,128.79,128.42,1 26.73,126.36,125.80,122.33,86.73,83.26,54.84,53.20,52.35,49.90,29.20.

[0124] Embodiment 18

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

[0126] Under air atmosphere, 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) and 0.15 mmol of DBU were added to a 25 mL pressure tube in sequence, followed by reaction at 100° C. for 12 hours to generate a mixed product. The reaction product was concentrated under reduced pressure to obtain a crude product. The crude product was separated and extracted on a silica gel (200 mesh) column using a mixed solution of petroleum ether and ethyl acetate (3:1 to 20:1) as an eluent. The eluent was collected and dried to obtain 45.1 mg of 1-phenylpropan-2-yl 2-diazo-3-(3,4-dihydroisoquinolin-2(1H)-yl) propionate (3aj) in a yield of 41%.

[0127]

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

[0129] 1 H NMR (500MHz, CDCl3) δ7.33-7.27(m,2H),7.22(dd,J=7.3,3.0Hz,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=6.8Hz,3H); 13 C NMR (126MHz, CDCl3) δ166.57,137.59,134.52,134.09,129.58,128.77,128.45,1 26.72,126.62,126.32,125.76,72.23,54.75,52.27,49.77,42.63,29.22,19.94.

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: Where: R 1 , R 2 is selected from one of alkyl, cycloalkyl, alkoxy, phenyl or benzyl, R 3 It is selected from one of an alkyl group, a cycloalkyl group, a phenyl group, a benzyl group, an alkylbenzene group or an unsaturated hydrocarbon group.

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

150.

3. The method for preparing the β-amino-α-diazo derivative according to claim 1, characterized in that: The structural formula of the amine compound is shown in Formula III to Formula VII: Where R 1 , R 2 One selected from alkyl, cycloalkyl, alkoxy, phenyl or benzyl.

4. The method for preparing the β-amino-α-diazo derivative according to claim 1, characterized in that: The structural formula of the α-diazocarbonyl compound is shown in Formula IX: Among them, R 3 It is selected from one of an alkyl group, a cycloalkyl group, a phenyl group, a benzyl group, an alkylbenzene group or an unsaturated hydrocarbon group.

5. The method for preparing the β-amino-α-diazo derivative according to claim 1, characterized in that: 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.

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

7. The method for preparing the β-amino-α-diazo derivative according to claim 1, characterized in that: In the column chromatography separation and purification, first use a 200-300 mesh silica gel column for separation, and then use a mixed solution 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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