Preparation method of tetrahydronaphthyridine compound and intermediate thereof

Abstract

The application provides a preparation method of tetrahydronaphthyridine compounds and intermediates thereof, and particularly relates to a preparation method of a compound of formula I and intermediates thereof, wherein the total yield of six-step reaction can reach 30%, the reaction operation is simple, the reaction condition is mild, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, specifically to a method for preparing tetrahydronaphthidine compounds and its intermediates. Background Technology

[0002] Tetrahydronaphthidine compounds have received increasing attention in the field of medicinal chemistry as relatively novel drug fragments. Among them, 1,2,3,4-tetrahydro-2,7-naphthidine, especially 6-chloro-1,2,3,4-tetrahydro-2,7-naphthidine or its hydrochloride, have been used in the synthesis of compounds targeting multiple drugs.

[0003]

[0004] For example, in the patent publication WO2021191838A1, it is used to prepare GABA. A α5 receptor modulators are used in the preparation of VEGFR kinase inhibitors in US Patent 9296747B1 and in the preparation of PED10 inhibitors in Patent Publication WO2014177977A1, etc.

[0005] There are no reports in the existing literature on the preparation of 6-chloro-1,2,3,4-tetrahydro-2,7-naphthidine or its hydrochloride, which limits its further application in the field of drug discovery. Summary of the Invention

[0006] This invention provides, in one aspect, a compound of formula III, which can be further used to prepare a compound of formula I.

[0007]

[0008] On the other hand, the present invention also provides a method for preparing a compound of formula III, characterized by comprising the following steps:

[0009]

[0010] Compound II reacts with diethyl malonate under alkaline conditions to give compound III.

[0011] In some embodiments, the alkaline reagent 1 is selected from potassium carbonate, cesium carbonate, or sodium hydroxide.

[0012] In some embodiments, the alkaline reagent 1 is potassium carbonate.

[0013] In some implementations, the reaction temperature is 70–80°C.

[0014] On the other hand, the present invention also provides a method for preparing a compound of formula I, characterized by comprising the following steps:

[0015]

[0016] In step one, alkaline reagent 1 is selected from potassium carbonate, cesium carbonate or sodium hydroxide, and the reaction temperature is 70-80℃;

[0017] Step 2: Alkaline reagent 2 is selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, or lithium chloride;

[0018] Step 3: The reducing agent is selected from the sodium borohydride / BF3·THF system, sodium borohydride·CDI system, sodium borohydride·lithium chloride system, or lithium aluminum tetrahydrogen.

[0019] In step four, alkaline reagent 3 is selected from triethylamine, DIEA, or DBU;

[0020] In step five, alkaline reagent 4 is selected from potassium carbonate or triethylamine, and the equivalent ratio of potassium iodide to compound VI is 0.2 to 0.5:1.

[0021] In step six, the reaction temperature is 80–100℃.

[0022] In some implementations, the alkaline reagent 1 in step one is potassium carbonate, and the reaction temperature is 70–80°C.

[0023] In some implementations, the alkaline reagent 2 in step two is lithium hydroxide; and the reducing agent in step three is a sodium borohydride / BF3·THF system.

[0024] In some implementations, the alkaline reagent 3 in step four is triethylamine; and the alkaline reagent 4 in step five is potassium carbonate.

[0025] In some implementations, the reaction temperature in step six is ​​85–90°C.

[0026] The technical solution of this invention fills the technical gap in the preparation of compound I in the prior art. The total yield of the six-step reaction can reach 30%. The reaction operation is simple, the conditions are mild, and it is suitable for industrial production.

[0027] The abbreviations of some of the reaction reagents involved in this invention are shown below:

[0028] DBU: 1,8-diazabicycloundec-7-ene

[0029] CDI: Carbonyldiimidazole

[0030] DIEA: N,N-Diisopropylethylamine

[0031] MTBE: Methyl tert-butyl ether

[0032] EsCl: Ethylsulfonyl chloride Detailed Implementation

[0033] Example 1

[0034] Step 1:

[0035]

[0036] DMF (16 L) and compound II (4000 g, 18.17 mol, 1.0 eq.) were sequentially added to a 50 L reactor, followed by potassium carbonate (7537 g, 54.53 mol, 3.0 eq.). Diethyl malonate (3494 g, 21.81 mol, 1.2 eq.) was added dropwise at 65 °C. After the addition was complete, the reaction mixture was reacted at 70–75 °C for 14 h. The reaction solution was poured into ice water (45 kg), and the pH was adjusted to 6–7 with concentrated hydrochloric acid. MTBE (20 L) was added to the system, and the mixture was stirred and separated. The aqueous phase was extracted with MTBE (15 L), and the organic phases were combined. The organic phase was evaporated to dryness to obtain compound III (6.8 kg, crude product yield 108%). LC-MS: [M+H] + =344.1.

[0037] Step Two:

[0038]

[0039] Compound III (7029 g, 20.44 mol, 1.0 eq.), methanol (21 L), water (21 L), and LiOH·H₂O (4290 g, 102.23 mol, 5.0 eq.) were added to a reaction vessel and reacted at 65 °C for 1 h. After the reaction was complete, the methanol was evaporated to dryness in a water bath at 50-55 °C, and the temperature was lowered to 0-10 °C. Concentrated hydrochloric acid was added dropwise until the pH reached 2-3, precipitating the crude product of compound IV. The crude product was filtered, washed with water, and dried to obtain compound IV (3200 g, yield 72.6%).

[0040] Step 3:

[0041]

[0042] THF (30 L) and compound IV (2000 g, 9.277 mol, 1 eq.) were added to a reaction vessel. Sodium borohydride (1053 g, 27.83 mol, 3 eq.) was added in portions at 10 °C, and the mixture was stirred for 30 minutes after the addition was complete. Boron trifluoride tetrahydrofuran complex (3894 g, 27.83 mol, 3 eq.) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 20 °C for 11 hours. The reaction was quenched with sodium hydroxide aqueous solution, and the reaction solution was collected. Sodium chloride (1000 g) was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 L), and the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound V (2.1 kg, exceeding the theoretical yield).

[0043] Steps four / five:

[0044]

[0045] Tetrahydrofuran (24 L) and compound V (1900 g, 10.12 mol, 1 eq.) were added to a reaction vessel. Under nitrogen protection, triethylamine (2561 g, 25.31 mol, 2.5 eq.) was added at 1 °C. EsCl (2863 g, 22.27 mol, 2.2 eq.) was added dropwise at -5 to 5 °C. After the addition was complete, the reaction was maintained at this temperature for 10 minutes, and then proceeded directly to the next reaction step. KI (335.9 g, 2.02 mol, 0.2 eq.) and potassium carbonate (3498 g, 25.31 mol, 2.5 eq.) were added to the system. 2,4-Dimethoxybenzylamine (1521 g, 9.11 mol, 0.9 eq.) was added dropwise at 0-10 °C. After the addition was complete, the reaction was carried out at room temperature for 12 hours. Filter, desolventize the filtrate at 45°C, wash the precipitated solid with acetonitrile (5 L), and dry to obtain compound VII (1400 g, two-step yield 43.3%).

[0046] Step Six:

[0047]

[0048] Trifluoroacetic acid (5.4 L) was added to a reaction vessel, and compound VII (2740 g, 8.59 mol, 1 eq.) was added in portions at 40 °C. After the addition was complete, triethylsilane (1199 g, 10.31 mol, 1.2 eq.) was added, and the system temperature was raised to 85-90 °C for 4 h. The reaction was quenched by adding water (15 L) and 50% sodium hydroxide aqueous solution (4 L). DCM (12 L) was added and the mixture was separated. The aqueous phase was extracted with DCM (10 L), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Acetone (14 L) was added, and a methanol solution of hydrochloric acid (15-17%) was added dropwise at 25 °C to adjust the pH to 2-3, precipitating a solid. The filter cake was washed with acetone (1 L * 2) and dried to obtain compound I (1525.8 g, yield 86%). 1 H-NMR (400MHz, DMSO) δ (ppm): 9.91 (brs, 2H), 8.31 (s, 1H), 7.46 (d, 1H), 4.95 (s, 2H), 4.28 (m, 2H), 3.06 (m, 2H). LC-MS:[M+H] + =169.1. HPLC: 97.08%.

[0049] Comparative Example 1

[0050] Following the method in Example 1, screening experiments were conducted on the reaction conditions for each step, and the results are shown in Tables 1-5.

[0051] Table 1. Screening of experimental conditions in Step 1

[0052]

[0053] Table 2. Screening of experimental conditions in step two.

[0054]

[0055] Table 3. Screening of experimental conditions in step three.

[0056]

[0057]

[0058] Table 4. Screening of experimental conditions for steps four / five.

[0059]

[0060] Table 5. Screening of experimental conditions in step five.

[0061]

Claims

1. A method for preparing a compound of formula I, characterized in that... It includes the following steps: In step one, alkaline reagent 1 is selected from potassium carbonate, and the reaction temperature is 70-80℃; Step 2: Alkaline reagent 2 is selected from lithium hydroxide; the solvent is a mixture of methanol and water. Step 3: The reducing agent is selected from the sodium borohydride / BF3·THF system; In step four, alkaline reagent 3 is selected from triethylamine; In step five, alkaline reagent 4 is selected from potassium carbonate, and the equivalent ratio of potassium iodide and compound VI is 0.2 to 0.5:

1. In step six, the reaction temperature is 80–100℃.

2. The preparation method according to claim 1, characterized in that, The reaction temperature in step six is ​​85–90°C.

Images