Synthesis method of steroid chiral amine

Abstract

The invention relates to a synthesis method of steroid chiral amine, which comprises the following steps: step 1, dissolving timosaponin in a first organic solvent, and reacting under the conditions of azide, phosphine ligand and azo reagent to form an intermediate (1) as shown in the formula (1); 2, dissolving the intermediate (1) in a second organic solvent, and carrying out a reduction reaction under the catalysis of a catalyst to obtain the steroid chiral amine as shown in a formula (2), the # imgabs 1 # is simple and convenient to operate and mild in condition, avoids the high-risk and explosive process of sodium azide in the prior art, avoids the use of a strong alkali catalyst, is more environment-friendly, has low requirements on production equipment, and can realize industrial production under normal temperature and normal pressure conditions; the reaction is less in three wastes and is a green process; conversion is achieved through two-step reaction, the total molar yield can reach 85.5%, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates and organic chemical intermediates, and particularly relates to a method for synthesizing steroidal chiral amines. Background Art

[0002] Steroidal chiral amines are an important class of pharmaceutical intermediates with a wide range of applications. For example, literature reports that they can be used to synthesize depression drugs (WO2019129176A1, CN108264535A) and anticancer drugs (WO2020062883A1). As an important unit of drug molecular skeleton and biologically active compounds, sapogenin is widely used. The chiral amines constructed are an important step in the synthesis of drug molecules. At present, the chiral synthesis is still limited. There are many synthesis methods for R-type amine compounds.

[0003] For example:

[0004]

[0005] The method reported (CN 108264535A) uses sodium azide to synthesize azides, but the reaction yield is low. Sodium azide is explosive and dangerous in large quantities, so it is not suitable for industrial scale-up. The reduction method of triphenylphosphine-tetrahydrofuran-water produces a lot of three wastes and is not environmentally friendly.

[0006] Therefore, it is necessary to develop new synthetic methods for steroidal R-type chiral amines. Summary of the invention

[0007] In view of the problems existing in the prior art, the present invention provides a method for synthesizing chiral steroids. The method is simple to operate, has mild conditions, produces little three wastes, and is suitable for industrial production.

[0008] In order to achieve the above object, the present invention provides a method for synthesizing steroidal chiral amines, the main features of which are as follows:

[0009] Step 1: dissolving sapogenin in a first organic solvent, and reacting it under the conditions of an azide, a phosphine ligand and an azo reagent to form an intermediate (1) as shown in formula (1): (2aR, 4R, 5', 6aS, 8aS, 8bR, 9S, 10R, 11aS, 12aS, 12bR)-4-azido-5', 6a, 8a, 9-tetramethyldicosyl spiro[naphtho[2', 1': 4, 5]indeno[2, 1-b]furan-10, 2'-pyran];

[0010]

[0011] Step 2: dissolving the intermediate (1) in a second organic solvent, and subjecting it to a reduction reaction under the catalysis of a catalyst to obtain a steroidal chiral amine (2aR, 4R, 5', 6aS, 8aS, 8bR, 9S, 10R, 11aS, 12aS, 12bR)-5', 6a, 8a, 9-tetramethyl docosyl spiro[naphtho[2', 1': 4, 5] indeno[2, 1-b] furan-10, 2'-pyran]-4-amine as shown in formula (2);

[0012]

[0013] Preferably, the azo reagent is one or more of diethyl azodicarboxylate (DEAD), dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate, azodimethoxyisoheptanenitrile, diisopropyl azodicarboxylate, dimethyl azodiisobutyrate, dibenzyl azodicarboxylate, and bis(trichloroethyl) azodicarboxylate;

[0014] The phosphine ligand is one or more of triphenylphosphine, tributylphosphine and tri-tert-butylphosphine;

[0015] The azide is one or more of lithium azide, sodium azide, trimethylsilyl azide, benzene azide, diphenylphosphoryl azide (DPPA), ammonium azide, p-toluenesulfonyl azide, and di-tert-butyl azidodicarboxylate.

[0016] Preferably, the molar ratio of the azo reagent to timosaponin is 0.5:1-3:1; the molar ratio of the azide to timosaponin is 1:1-5:1; and the molar ratio of the phosphine ligand to timosaponin is 1:1-5:1.

[0017] Preferably, the first organic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, ether, dichloromethane, toluene, ethyl acetate, acetonitrile, and DMF;

[0018] The second organic solvent is one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, benzene, toluene, dichloromethane, water, isopropanol, and acetone.

[0019] Preferably, in the step 1, the reaction temperature is -10°C to 80°C, preferably room temperature; and the reaction time is 0.5 hour to 48 hours.

[0020] Preferably, in step 2, the catalyst is one or more of palladium carbon, Raney nickel, iron, zinc, tin, platinum dioxide, lithium aluminum hydroxide, triphenylphosphine / water, palladium / barium sulfate, and the molar ratio of the catalyst to the intermediate (1) is 0.05:1 to 1:1.

[0021] Preferably, in step 2, the reaction temperature is 0°C to 100°C, preferably room temperature; and the reaction time is 0.5 hour to 48 hours.

[0022] The beneficial effects of the steroid chiral synthesis method of the present invention are:

[0023] The operation is simple and the conditions are mild, and the high-risk and explosive process of sodium azide in the existing process is avoided, and the use of strong base catalysts is avoided, which is more environmentally friendly, has low requirements on production equipment, and can realize industrial production under normal temperature and pressure conditions; there are less three wastes in the reaction, and it is a green process; the present invention realizes conversion through two-step reaction, and the total molar yield can reach 85.5%, which is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a graph showing the purity results of the intermediate (1) in Example 1 of the present invention.

[0025] Figure 2 This is the hydrogen spectrum of the intermediate (1) in Example 1 of the present invention.

[0026] Figure 3 This is a graph showing the purity of the steroidal chiral amine (2) in Example 2 of the present invention.

[0027] Figure 4 This is the hydrogen spectrum of the steroidal chiral amine (2) in Example 2 of the present invention. DETAILED DESCRIPTION

[0028] In order to make the technical means, creative features, objectives and effects achieved by the present invention easy to understand, the present invention is further explained below with reference to specific diagrams.

[0029] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents or consumables involved can be obtained through commercial channels unless otherwise specified.

[0030] The present invention has been proved through a large number of experiments that the use of organic azide, azo reagent and phosphine ligand can effectively improve the yield, shorten the reaction time, and the conditions are mild. The yield of step 1 reaches more than 90%. The reaction mechanism of its synthesis is as follows:

[0031]

[0032] Example 1

[0033] Preparation of intermediate (1)

[0034]

[0035] In a 500 ml three-necked flask, add sapogenin (41.5 g, 0.1 mol), DPPA (27.5 g, 0.1 mol) and triphenylphosphine (26.2 g, 0.1 mol), add 250 ml tetrahydrofuran (THF), cool to 0 degrees, protect with nitrogen, add DEAD (17.4 g, 0.1 mol) dropwise at 0 degrees, stir at room temperature for 6 hours, and complete the reaction by TLC detection. The reaction solution is directly spin-dried and eluted with PE / EA to obtain (1) with a yield of 85%. The purity of the intermediate (1) is as follows: Figure 1 As shown, NMR Figure 2 shown.

[0036] Regarding the preparation of intermediate (1), similar to the above-mentioned synthesis conditions, different conditions as shown in Table 1 were also screened, and the results obtained are shown in Table 1.

[0037] Table 1

[0038] batch Reagent screening Organic solvents Temperature ℃ Time (h) Yield (%) 1 PPh3,DBU,DPPA THF Room temperature 6 0 2 PPh3,DIAD,DPPA THF Room temperature 6 75 3 PPh3,DEAD,DPPA THF Room temperature 6 85 4 PPh3,DBAD,DPPA THF Room temperature 6 60 5 PPh3,TsOH,DPPA THF Room temperature 6 0 6 PPh3,Et3N,DPPA THF Room temperature 6 0 7 DEAD,DPPA THF Room temperature 6 0 8 PPh3,DPPA THF Room temperature 6 0 9 PPh3,TMSN3,DBU THF Room temperature 6 30 10 DBU,DPPA THF Room temperature 6 0

[0039] Under the same conditions as in Example 1, according to the results in Table 1, batch 3 catalyst was selected to screen its different ratios. Specifically, batch 4 was used to explain the ratio in the table. The amount of timosaponin was 0.1 mol, and the ratio of 2:2:2 meant that all three components were 0.2 mol. The results are shown in Table 2.

[0040] Table 2

[0041] batch PPh3:DEAD:DPPA Yield (%) 1 0.5：0.5：0.5 50 2 1：1：1 85 3 1.5：1.5：1.5 88 4 2：2：2 90 5 2：1.5：2 86

[0042] Under the same conditions as in Example 1, the effects of different organic solvents on the yield were tested according to Table 1 and Table 2. The results are shown in Table 3.

[0043] Table 3

[0044] batch Solvents Yield (%) 1 Dichloromethane 60 2 Toluene 70 3 Tetrahydrofuran 85 4 Methyltetrahydrofuran 83 5 Ethyl acetate 70

[0045] Under the same conditions as in Example 1, the effects of different phosphine ligands on the yield were tested. The results are shown in Table 4.

[0046] Table 4

[0047] batch Phosphine ligand Yield (%) 1 Triphenylphosphine 85 2 Tributylphosphine 75 3 Tri-tert-butylphosphine 70

[0048] Under the same conditions as in Example 1, the effect of different reaction times on the yield was tested, and the results are shown in Table 5.

[0049] Table 5

[0050] batch Time (hours) Yield (%) 1 2 30 2 6 85 3 10 85 4 24 82

[0051] Under the same conditions as in Example 1, the effect of different reaction temperatures on the yield was tested, and the results are shown in Table 6.

[0052] Table 6

[0053] batch Temperature(℃) Yield (%) 1 -10 30 2 0 80 3 Room temperature 85 4 80 75

[0054] Example 2

[0055] Steroidal chiral amines (2)

[0056]

[0057] In a 500 ml three-necked flask, add the intermediate (1) (44 g, 0.1 mol) at once, add 300 ml of tetrahydrofuran to dissolve, replace with nitrogen, add 4.4 g of palladium carbon, and provide hydrogen with a hydrogen bag. React at room temperature for 6 hours. TLC detection shows that the reaction is complete. Filter the reaction solution to remove the palladium carbon, spin dry, elute with PE / EA and recrystallize through a column to obtain a steroidal chiral amine (2) with a yield of 95%. The purity of the steroidal chiral amine (2) is as follows: Figure 3 As shown, NMR Figure 4 shown.

[0058] Regarding the preparation of steroidal chiral amine (2), similar to the above-mentioned synthesis conditions, different conditions as shown in Table 7 were also screened, and the results obtained are shown in Table 7.

[0059] Table 7

[0060] batch catalyst temperature Time (hours) Yield (%) 1 Pd / C Room temperature 6 95 2 Pd / C Room temperature 12 95 3 <![CDATA[PPh3-H20]]> Room temperature 6 60 4 Raney Nickel Room temperature 6 80

[0061] In this specification, the present invention has been described with reference to specific embodiments thereof. However, it is apparent that various modifications and variations may be made without departing from the spirit and scope of the present invention. Therefore, the specification and drawings should be regarded as illustrative rather than restrictive.

Claims

1. A method for synthesizing a steroidal chiral amine, characterized in that: These include: Step 1: dissolving timosaponin in a first organic solvent and reacting it in the presence of an azide, a phosphine ligand and an azo reagent to form an intermediate (1) as shown in formula (1); Step 2: dissolving the intermediate (1) in a second organic solvent and subjecting it to a reduction reaction under the catalysis of a catalyst to obtain a steroidal chiral amine as shown in formula (2); 2. The method for synthesizing a steroidal chiral amine according to claim 1, characterized in that: The azo reagent is one or more of diethyl azodicarboxylate, dimethyl azodicarboxylate, di-tert-butyl azodicarboxylate, azodimethoxyisoheptanenitrile, diisopropyl azodicarboxylate, dimethyl azodiisobutyrate, dibenzyl azodicarboxylate, and di(trichloroethyl) azodicarboxylate; The phosphine ligand is one or more of triphenylphosphine, tributylphosphine and tri-tert-butylphosphine; The azide is one or more of lithium azide, sodium azide, trimethylsilyl azide, benzene azide, diphenylphosphoryl azide, ammonium azide, p-toluenesulfonyl azide, and di-tert-butyl azidodicarboxylate.

3. The method for synthesizing steroidal chiral amines according to claim 1, characterized in that: The molar ratio of the azo reagent to the timosaponin is 0.5:1-3:1; the molar ratio of the azide to the timosaponin is 1:1-5:1; and the molar ratio of the phosphine ligand to the timosaponin is 1:1-5:

1.

4. The method for synthesizing steroidal chiral amines according to claim 1, characterized in that: The first organic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, ether, dichloromethane, toluene, ethyl acetate, acetonitrile, and DMF; The second organic solvent is one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, benzene, toluene, dichloromethane, water, isopropanol, and acetone.

5. The method for synthesizing steroidal chiral amines according to claim 1, characterized in that: In the step 1, the reaction temperature is -10°C to 80°C; the reaction time is 0.5 hour to 48 hours.

6. The method for synthesizing steroidal chiral amines according to claim 1, characterized in that: In the step 2, the catalyst is one or more of palladium carbon, Raney nickel, iron, zinc, tin, platinum dioxide, lithium aluminum hydroxide, triphenylphosphine / water, palladium / barium sulfate, and the molar ratio of the catalyst to the intermediate (1) is 0.05:1 to 1:

1.

7. The method for synthesizing steroidal chiral amines according to claim 1, characterized in that: In the step 2, the reaction temperature is 0°C to 100°C; the reaction time is 0.5 hour to 48 hours.

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