Preparation method of a pomalidomide derivative

Abstract

The present invention discloses a preparation method of pomalidomide derivatives. The following reaction conditions are used: an organic base and an organic amine raw material shown in formula (II) are added to an organic solvent containing a fluorinated thalidomide raw material shown in formula (I) heated to 140-180 °C. After the reaction is completed, the reaction solution is post-treated and then separated and purified to obtain a pomalidomide derivative shown in formula (III). The reaction time of this preparation method only needs 5-10 minutes, and the yield ranges from 85% to 95%. It solves the problems of long reaction time and difficult product purification in the existing preparation methods, and has the advantages of extremely short reaction time, high yield, easy product purification, and stable process conditions.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a pomalidomide derivative. Background Art

[0002] At present, most drugs are protein inhibitors, which inhibit the activity of pathogenic proteins by specifically binding to them to achieve therapeutic effects. However, the number of pathogenic proteins that can be bound by available inhibitors is limited, less than 20% of the total number of potential pathogenic proteins, and 80% of pathogenic proteins are undruggable targets. In the 1970s and 1980s, Israeli scientists Aaron Sichanova, Avram Hershko and American scientist Irwin Ross discovered ubiquitin-mediated protein degradation after years of research. They won the 2004 Nobel Prize for this.

[0003] Ubiquitin is a polypeptide composed of 76 amino acids. It can form a strong covalent bond with proteins. Once the protein is marked by it, it will be sent to the "garbage disposal plant" in the cell-proteasome for degradation. TPD technology is a new technology that specifically identifies target proteins and directly degrades target proteins using the inherent protein degradation pathway in the cell. This is equivalent to finding the pathogenic "target" in the cell and eradicating them. The concept of targeted protein degradation was first proposed in 1999. In 2001, scholars proposed a more specific concept of protein degradation targeted chimera (PROTAC) and synthesized the first chimeric molecule for targeted protein degradation. At present, the field of TPD has developed technologies such as PROTAC, molecular glue, degradation tags, lysosome targeting chimeras, and autophagosome binding compounds, which greatly expands the range of degradable target proteins. Among them, PROTAC is a hybrid bifunctional small molecule compound, which consists of three parts: target protein ligand, linker and E3 ligase ligand. The two ligands in the structure are connected by linker to form a "three-body" polymer - target protein ligand-linker-E3 ligand. It shortens the distance between the target protein and the E3 ubiquitin ligase in the cell, and uses the ubiquitin-proteasome pathway to specifically degrade the target protein.

[0004] The preparation method of the present invention can be used to synthesize pomalidomide E3 ligase ligands containing Linker, and the ligands of pomalidomide E3 ligase containing Linker can be further used to synthesize PROTAC molecules. At present, the synthesis of E3 ligase ligands of pomalidomide is mainly obtained by condensation of fluorinated thalidomide and organic amine compounds (Chem. Sci., 2021, 12, 4519–4525; Med. Chem. Commun., 2019, 10, 1037-1041). However, the current method has problems such as long reaction time, incomplete conversion of raw materials, many by-products, and difficult separation and purification of products due to the close polarity of by-products, raw materials and products. Therefore, it is urgent in the art to develop a method for quickly preparing ligands of pomalidomide E3 ligase containing Linker. Summary of the Invention

[0005] The object of the present invention is to provide a preparation method for quickly preparing pomalidomide derivatives, which can effectively solve the problems of long reaction time, many by-products, incomplete conversion of raw materials, incomplete conversion of raw materials and many by-products resulting in difficult separation and purification of products in the preparation of ligands of existing pomalidomide E3 ligase containing Linker.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A preparation method of a pomalidomide derivative, characterized in that an organic base and an organic amine raw material shown in formula (II) are added to an organic solvent containing a fluorinated thalidomide raw material shown in formula (I) at a temperature of 140-180 °C for reaction. After the reaction is completed, a reaction solution is obtained. The reaction solution is post-treated and then separated and purified to obtain a thalidomide derivative shown in formula (III). The reaction formula is as follows:

[0008]

[0009] Further, the organic solvent is a mixed solvent of one or more of N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO).

[0010] Further, the organic base is a tertiary amine organic amine.

[0011] Further, R in the raw material shown in formula (II) 1 is an alkyl group containing 1-20 carbons, an alkyl group with an amino group or a hydroxyl group, or an oxaalkyl group; R 2 is hydrogen, an alkyl group containing 1-20 carbons, or an oxaalkyl group; In particular, R 1 and R 2 can form a ring.

[0012] Furthermore, the raw materials of formula (I) are selected from the structures shown below:

[0013]

[0014] Furthermore, the organic amine raw materials of formula (II) are selected from the structures shown below:

[0015]

[0016] Wherein, m is any integer from 1 to 20; n is any integer from 1 to 8; o is any integer from 0 to 5; PG is a protecting group of the amino group.

[0017] Furthermore, the organic amine raw materials of formula (II) are selected from the structures shown below:

[0018]

[0019] Wherein, m is any integer from 1 to 20; n is any integer from 1 to 8; o is any integer from 0 to 5.

[0020] Furthermore, the organic amine raw materials of formula (II) are selected from the structures shown below:

[0021]

[0022] Furthermore, the organic base is one or more of diisopropylethylamine (DIPEA), triethylamine (Et3N), and tri-n-butylamine ( n Bu3N); the reaction temperature range is 150 - 170 °C; the organic solvent is dimethyl sulfoxide (DMSO).

[0023] Due to the adoption of the above technical solution, the present invention has the following advantages:

[0024] 1. For the preparation method of the present invention, the reaction time is short (less than 10 minutes, far shorter than the reaction time required by the existing preparation methods), and the yield is high (>85%), and the E3 ligand containing linker can be rapidly prepared.

[0025] 2. The preparation method of the present invention can completely convert the fluorinated lenalidomide raw materials of formula (I) without residue of the fluorinated lenalidomide raw materials of formula (I). Since the polarities of the raw materials and the product are close, it is easier to separate and purify the product after the reaction of the fluorinated lenalidomide raw materials of formula (I) is complete, with few by-products and complete conversion.

[0026] Other advantages, objects and features of the present invention will be set forth in part in the following description, and in part will be obvious to those skilled in the art upon examination of the following, or may be learned from the practice of the present invention. The objects and other advantages of the present invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The drawings of the present invention are described as follows:

[0028] Figure 1 It is a synthetic flow chart of the present invention.

[0029] Figure 2 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 2.

[0030] Figure 3 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 3.

[0031] Figure 4 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 4.

[0032] Figure 5 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 5.

[0033] Figure 6 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 6.

[0034] Figure 7 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 7.

[0035] Figure 8 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 8.

[0036] Figure 9 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 9.

[0037] Figure 10 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 10.

[0038] Figure 11 It is the nuclear magnetic resonance spectrum of the compound prepared in Example 11. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention will be further described below with reference to the drawings and examples. However, it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0040] Example 1: A preparation method of pomalidomide derivatives, and the synthetic flow chart is as Figure 1 shown.

[0041] The synthesis steps are as follows:

[0042] To the dimethyl sulfoxide (10 mL) solvent containing 4-fluoro, 5-fluoro or 5,6-difluoro thalidomide (1.81 mmol) heated to 160 °C, an organic base (5.43 mmol) and the organic amine raw material shown in formula (II) (1.90 mmol) were added, and the reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature (cooling with cold water could accelerate the cooling process). The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water (ratio 1:4) for extraction. After extracting the aqueous phase 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After concentration, the washed organic phase was subjected to silica gel column chromatography (100 - 200 mesh) to obtain the pomalidomide derivative shown in formula (III) by separation and purification;

[0043] The reaction time of this preparation method only needs 5 - 10 minutes, and the yield range is 80 - 95%.

[0044] Example 2: Preparation of Pomalidomide - C2 - NHBoc

[0045]

[0046] To the dimethyl sulfoxide (10 mL) solvent containing 4-fluoro thalidomide (500 mg, 1.81 mmol) heated to 160 °C, diisopropylethylamine (946 μL, 5.43 mmol) and N - tert - butoxycarbonyl - 1,2 - ethylenediamine (301 μL, 1.90 mmol) were added, and the reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After extracting the aqueous phase 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After concentration, the washed organic phase was subjected to silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:2 - 1:1) to obtain 693 mg of the yellow Pomalidomide - C2 - NHBoc pomalidomide derivative;

[0047] The reaction time of this preparation method only needs 5 minutes, and the yield is 92%;

[0048] Figure 2 For the nuclear magnetic resonance of the product 1 1H spectrum; Product characterization: 1HNMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.64–7.49 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 2H), 6.72 (t, J = 6.0 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 3.37 (dd, J = 11.6, 5.4 Hz, 2H), 3.12 (dd, J = 11.6, 5.8 Hz, 2H), 2.89 (m, 1H), 2.56 (dd, J = 21.3, 11.0 Hz, 2H), 2.09–1.97 (m, 1H), 1.37 (s, 9H).

[0049] Example 3: Preparation of Pomalidomide-C4-NHBoc

[0050]

[0051] To dimethyl sulfoxide (10 mL) solvent containing 4-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C was added diisopropylethylamine (946 μL, 5.43 mmol) and N-Boc-1,4-butanediamine (364 μL, 1.90 mmol). The reaction was carried out for 5 minutes. After completion of the reaction, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of ethyl acetate and 200 mL of water with a ratio of 1:4 for extraction. After extracting the aqueous phase 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After concentration, the washed organic phase was subjected to silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:3 - 1:2) to obtain 756 mg of yellow Pomalidomide-C4-NHBoc pomalidomide derivative;

[0052] The reaction time of this preparation method is only 5 minutes, and the yield is 94%;

[0053] Figure 3 It is a nuclear magnetic resonance 1 H spectrum; Product characterization: 11H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.57 (dd, J = 8.4, 7.3 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.85 (t, J = 5.6 Hz, 1H), 6.56 (t, J = 5.9 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.30 (dd, J = 13.1, 6.6 Hz, 2H), 2.95 (dd, J = 12.8, 6.6 Hz, 2H), 2.91–2.80 (m, 1H), 2.65–2.51 (m, 2H), 2.03 (m, 1H), 1.59–1.49 (m, 2H), 1.45 (dd, J = 14.1, 6.8 Hz, 2H), 1.37 (s, 9H).

[0054] Example 4: Preparation of Pomalidomide-C6-NHBoc

[0055]

[0056] To dimethyl sulfoxide (10 mL) solvent containing 4-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C was added diisopropylethylamine (946 μL, 5.43 mmol) and N-Boc-1,6-hexanediamine (426 μL, 1.90 mmol). The reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After the aqueous phase was extracted 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After the washed organic phase was concentrated, it was subjected to silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:4 - 1:3) to obtain 813 mg of yellow Pomalidomide-C4-NHBoc pomalidomide derivative;

[0057] The reaction time of this preparation method is only 5 minutes, and the yield is 95%;

[0058] Figure 4 For the product nuclear magnetic resonance 1 1H spectrum; Product characterization: 1HNMR(400MHz, DMSO) δ 11.11(s, 1H), 7.58(dd, J = 8.4, 7.3 Hz, 1H), 7.05(dd, J = 25.7, 7.8 Hz, 2H), 6.77(t, J = 5.4 Hz, 1H), 6.54(t, J = 5.8 Hz, 1H), 5.06(dd, J = 12.9, 5.4 Hz, 1H), 3.28(dd, J = 13.2, 6.6 Hz, 2H), 2.99–2.81(m, 3H), 2.66–2.53(m, 2H), 2.08–2.01(m, 1H), 1.56(m, 2H), 1.42–1.24(m, 14H).

[0059] Example 5: Preparation of Pomalidomide-PEG1-NHBoc

[0060]

[0061] To dimethyl sulfoxide (10 mL) solvent containing 4-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C, diisopropylethylamine (946 μL, 5.43 mmol) and tert-butyl [2-(2-aminoethoxy)ethyl]carbamate (379 μL, 1.90 mmol) were added, and the reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After extracting the aqueous phase 3 times, the organic phases were combined. The combined organic phase was washed once with saturated brine. After concentration, the washed organic phase was separated and purified by silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:2 - 1:1) to obtain 775 mg of yellow Pomalidomide-PEG1-NHBoc pomalidomide derivative;

[0062] The reaction time of this preparation method is only 5 minutes, and the yield is 93%;

[0063] Figure 5 For the nuclear magnetic resonance 1 H spectrum of the product; Product characterization: 1HNMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.58 (dd, J = 8.4, 7.2 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.79 (t, J = 5.6 Hz, 1H), 6.62 (t, J = 5.7 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.59 (t, J = 5.4 Hz, 2H), 3.45 (dt, J = 12.3, 5.7 Hz, 4H), 3.09 (q, J = 5.9 Hz, 2H), 2.89 (m, 1H), 2.64–2.52 (m, 2H), 2.04 (m, 1H), 1.36 (s, 9H).

[0064] Example 6: Preparation of Pomalidomide-PEG2-NHBoc

[0065]

[0066] To dimethyl sulfoxide (10 mL) solvent containing 4-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C, diisopropylethylamine (946 μL, 5.43 mmol) and tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (452 μL, 1.90 mmol) were added, and the reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After the aqueous phase was extracted 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After the washed organic phase was concentrated, it was subjected to silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:1) to obtain 849 mg of yellow Pomalidomide-PEG2-NHBoc pomalidomide derivative;

[0067] The reaction time of this preparation method only needs 5 minutes, and the yield is 93%;

[0068] Figure 6 For the nuclear magnetic resonance 1 H spectrum of the product; Product characterization: 1HNMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.66–7.52 (m, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.74 (t, J = 5.2 Hz, 1H), 6.61 (t, J = 5.6 Hz, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 3.62 (t, J = 5.3 Hz, 2H), 3.60–3.54 (m, 2H), 3.49 (ddd, J = 16.3, 7.9, 4.0 Hz, 4H), 3.38 (t, J = 6.0 Hz, 2H), 3.06 (dd, J = 11.7, 5.8 Hz, 2H), 2.89 (m, 1H), 2.57 (dd, J = 17.7, 10.5 Hz, 2H), 2.09–1.98 (m, 1H), 1.36 (s, 9H).

[0069] Example 7: Preparation of Pomalidomide-PEG3-NHBoc

[0070]

[0071] To dimethyl sulfoxide (10 mL) solvent containing 4-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C, diisopropylethylamine (946 μL, 5.43 mmol) and 1,1-dimethylethyl 13-amino-5,8,11-trioxa-2-azatridecanoate (529 μL, 1.90 mmol) were added, and the reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After extracting the aqueous phase 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After concentration, the washed organic phase was subjected to silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:1) to obtain 874 mg of yellow Pomalidomide-PEG3-NHBoc pomalidomide derivative;

[0072] The reaction time of this preparation method is only 5 minutes, and the yield is 88%;

[0073] Figure 7 For the nuclear magnetic resonance of the product 1 H spectrum;; Product characterization: 1HNMR(400MHz, DMSO) δ 11.11 (s, 1H), 7.58 (dd, J = 8.4, 7.3 Hz, 1H), 7.10 (dd, J = 42.2, 7.8 Hz, 2H), 6.68 (dt, J = 57.8, 5.6 Hz, 2H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.62 (t, J = 5.4 Hz, 2H), 3.57 (dd, J = 5.3, 2.7 Hz, 2H), 3.55–3.51 (m, 2H), 3.51–3.44 (m, 5H), 3.36 (t, J = 6.0 Hz, 3H), 3.05 (q, J = 5.9 Hz, 2H), 2.89 (m, 1H), 2.57 (dd, J = 20.1, 10.6 Hz, 2H), 2.11–1.95 (m, 1H), 1.36 (s, 9H).

[0074] Example 8: Preparation of Pomalidomide-PEG4-NHBoc

[0075]

[0076] (1) Experimental method

[0077] To the dimethyl sulfoxide (10 mL) solvent containing 4-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C, diisopropylethylamine (946 μL, 5.43 mmol) and 1,1-dimethylethyl 16-amino-5,8,11,14-tetraoxa-2-azahexadecanoate (604 μL, 1.90 mmol) were added, and the reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After the aqueous phase was extracted 3 times, the organic phases were combined. The organic phase was washed once with saturated brine, and after concentration, it was separated and purified by silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 2:1) to obtain 933 mg of yellow Pomalidomide-PEG4-NHBoc pomalidomide derivative;

[0078] The reaction time of this preparation method is only 5 minutes, and the yield is 87%;

[0079] Figure 8 For the nuclear magnetic resonance 1 H spectrum of the product;; Product characterization: 1HNMR(400MHz, DMSO) δ 11.11(s, 1H), 7.59(dd, J = 8.4, 7.3Hz, 1H), 7.15(d, J = 8.6Hz, 1H), 7.04(d, J = 7.0Hz, 1H), 6.75(t, J = 5.3Hz, 1H), 6.61(t, J = 5.5Hz, 1H), 5.06(dd, J = 12.9, 5.4Hz, 1H), 3.62(t, J = 5.3Hz, 2H), 3.59–3.44(m, 14H), 3.37(s, 2H), 3.05(dd, J = 11.8, 5.9Hz, 2H), 2.89(m, 1H), 2.57(dd, J = 19.8, 10.5Hz, 2H), 2.08–1.96(m, 1H), 1.37(s, 9H).

[0080] Example 9: Preparation of Pomalidomide-C2-OH

[0081]

[0082] To the dimethyl sulfoxide (10 mL) solvent containing 5-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C, diisopropylethylamine (946 μL, 5.43 mmol) and ethanolamine (115 μL, 1.90 mmol) were added. The reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After extracting the aqueous phase 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After the washed organic phase was concentrated, it was subjected to silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:2 - 1:1) to obtain 546 mg of yellow Pomalidomide-C2-OH pomalidomide derivative;

[0083] The reaction time of this preparation method only needs 5 minutes, and the yield is 95%;

[0084] Figure 9 For the nuclear magnetic resonance 1 H spectrum of the product; Product characterization: 1HNMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.63–7.53 (m, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.65 (t, J = 5.6 Hz, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.93 (t, J = 5.1 Hz, 1H), 3.60 (q, J = 5.4 Hz, 2H), 3.38 (d, J = 5.5 Hz, 1H), 2.89 (ddd, J = 17.4, 14.2, 5.2 Hz, 1H), 2.68–2.53 (m, 2H), 2.11–2.01 (m, 1H).

[0085] Example 10: Preparation of Pomalidomide-Piperazine

[0086]

[0087] To dimethyl sulfoxide (10 mL) solvent containing 5-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C was added diisopropylethylamine (946 μL, 5.43 mmol) and anhydrous piperazine (164 mg, 1.90 mmol). The reaction was carried out for 5 minutes. After completion of the reaction, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After extracting the aqueous phase 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After concentration, the washed organic phase was subjected to silica gel column chromatography (100 - 200 mesh, dichloromethane:methanol = 30:1 to 20:1) to obtain 527 mg of yellow Pomalidomide-Piperazine pomalidomide derivative;

[0088] The reaction time of this preparation method is only 5 minutes and the yield is 85%;

[0089] Figure 10 For the nuclear magnetic resonance of the product 1 1H spectrum; Product characterization: 1 HNMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 5.10 (dd, J = 12.9, 5.3 Hz, 1H), 3.32 (s, 1H), 3.20 (s, 4H), 2.87 (s, 5H), 2.57 (dd, J = 19.3, 10.2 Hz, 2H), 2.02 (dd, J = 11.9, 6.2 Hz, 1H).

[0090] Example 11: Preparation of Pomalidomide-5-C2-NHBoc

[0091]

[0092] To the dimethyl sulfoxide (10 mL) solvent containing 5-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C, diisopropylethylamine (946 μL, 5.43 mmol) and N-tert-butoxycarbonyl-1,2-ethylenediamine (301 μL, 1.90 mmol) were added, and the reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of ethyl acetate and 200 mL of water with a ratio of 1:4 for extraction. After extracting the aqueous phase 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After concentration, the washed organic phase was separated and purified by silica gel column chromatography (100-200 mesh, ethyl acetate: petroleum ether = 1:2 to 1:1) to obtain 716 mg of the yellow Pomalidomide-5-C2-NHBoc pomalidomide derivative;

[0093] The reaction time of this preparation method is only 5 minutes, and the yield is 95%;

[0094] Figure 11 For the product nuclear magnetic resonance 1 1H spectrum; Product characterization: 1 HNMR(400MHz,DMSO)δ11.07(s,1H),7.57(d,J=8.3Hz,1H),7.15(t,J=5.6Hz,1H),6.98(s,1H),6.93(t,J=5.5Hz,1H),6.86(dd,J=8.4,1.9Hz,1H),5.04(dd,J=12.9,5.4Hz,1H),3.24(dd,J=12.3,6.2Hz,2H),3.16–3.04(m,2H),2.88(m,1H),2.56(dd,J=17.9,10.6Hz,2H),1.99(s,1H),1.37(s,9H).

[0095] Comparative Example 1: Preparation of Pomalidomide-C2-NHBoc - Add all the raw materials at one time for heating reaction

[0096]

[0097] The dimethyl sulfoxide (10 mL) solvent containing 4-fluorothalidomide (500 mg, 1.81 mmol), diisopropylethylamine (946 μL, 5.43 mmol) and N-Boc-ethylenediamine (301 μL, 1.90 mmol) was heated from room temperature to 160 °C. It took 12 hours for the 4-fluorothalidomide raw material to be completely converted. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After the aqueous phase was extracted 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After the washed organic phase was concentrated, it was separated and purified by silica gel column chromatography (100 - 200 mesh, ethyl acetate:petroleum ether = 1:2 - 1:1) to obtain the Pomalidomide-C2-NHBoc pomalidomide derivative. The reaction time of this preparation method is 12 hours and the yield is 42%.

[0098] Comparative Example 2: Preparation of Pomalidomide-C2-NHBoc - Replace diisopropylethylamine with triethylamine

[0099] Triethylamine (758 μL, 5.43 mmol) and N-Boc-ethylenediamine (301 μL, 1.90 mmol) were added to the dimethyl sulfoxide (10 mL) solvent containing 4-fluorothalidomide (500 mg, 1.81 mmol) heated to 160 °C. The reaction was carried out for 5 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After the aqueous phase was extracted 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After the washed organic phase was concentrated, it was separated and purified by silica gel column chromatography (100 - 200 mesh, ethyl acetate:petroleum ether = 1:2 - 1:1) to obtain the Pomalidomide-5-C2-NHBoc pomalidomide derivative. The reaction time of this preparation method is only 5 minutes and the yield is 87%.

[0100] Comparative Example 3: Preparation of Pomalidomide-C2-NHBoc - Adjust the feeding order

[0101] To the dimethyl sulfoxide (10 mL) solvent containing N-Boc-1,2-ethylenediamine (301 μL, 1.90 mmol) heated to 160 °C, diisopropylethylamine (946 μL, 5.43 mmol) and 4-fluorothalidomide (500 mg, 1.81 mmol) were added. The reaction time required for complete conversion was 12 h. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After the aqueous phase was extracted 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After the washed organic phase was concentrated, it was subjected to silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:2 - 1:1) to separate and purify the Pomalidomide-C2-NHBoc pomalidomide derivative. The reaction time of this preparation method only needs 5 minutes, and the yield is 38%.

[0102] Comparative Example 4: Preparation of Pomalidomide-C2-NHBoc - The reaction temperature was 130 °C

[0103] To the dimethyl sulfoxide (10 mL) solvent containing N-Boc-1,2-ethylenediamine (301 μL, 1.90 mmol) heated to 130 °C, diisopropylethylamine (946 μL, 5.43 mmol) and 4-fluorothalidomide (500 mg, 1.81 mmol) were added. The reaction time required for complete conversion was 10 h. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into a mixed solvent of 200 mL of ethyl acetate and water with a ratio of 1:4 for extraction. After the aqueous phase was extracted 3 times, the organic phases were combined. The organic phase was washed once with saturated brine. After the washed organic phase was concentrated, it was subjected to silica gel column chromatography (100 - 200 mesh, ethyl acetate: petroleum ether = 1:2 - 1:1) to separate and purify the Pomalidomide-C2-NHBoc pomalidomide derivative. The reaction time of this preparation method only needs 5 minutes, and the yield is 77%.

[0104] Comparative Example 5: Comparison of the effects of the prior art and the present invention

[0105] Description of technical effects:

[0106]

[0107] Finally, it should be noted that the above are only the preferred experiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, for those skilled in the art, they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of pomalidomide derivatives, characterized in that, An organic base and an organic amine raw material shown in formula (II) are added to an organic solvent containing a fluorinated thalidomide raw material shown in formula (I) at a temperature of 160 °C for reaction. After the reaction is completed, a reaction solution is obtained. The reaction solution is post-treated and then separated and purified to obtain a thalidomide derivative shown in formula (III); Among them, the fluorinated thalidomide raw material shown in formula (I) is selected from the following structures: ； The organic amine raw material shown in formula (II) is selected from the following structures: ； The thalidomide derivative shown in formula (III) includes the following structures: The organic solvent is dimethyl sulfoxide; The organic base is one of triethylamine or N,N-diisopropylethylamine.

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