A method for preparing an indazole molecular building block and its application in drug synthesis

Abstract

The invention discloses a preparation method of an indazole molecular building block and application thereof in drug synthesis, and relates to the technical field of drug intermediate synthesis. O-carbonylaniline is used as a raw material, and the indazole molecular building block is reacted with a Boc-protected hydroxylamine derivative LgONHBoc or a hydroxylamine derivative LgONH2 to obtain the indazole molecular building block. The raw materials used in the invention are all industrial raw materials and are easy to obtain. There is no metal catalytic reaction, and the method is safe and reliable. Byproducts can be removed by simple alkali washing, and the product is easy to purify with a stable yield.

Description

Technical field:

[0001] The invention relates to the technical field of drug intermediate synthesis, and in particular to a method for preparing an indazole molecular building block and application thereof in drug synthesis. Background technology:

[0002] The indazole skeleton is a common building block in drugs and bioactive molecules. In recent years, compounds containing the indazole skeleton have been one of the most valuable synthetic targets, showing significant biological and pharmacological activities, such as axitinib, granisetron, lonidamine and other drugs, as well as common active molecules. Although this type of building block is widely used in drugs and candidate drug active molecules, its synthesis method is relatively small and has not received widespread attention.

[0003] The synthesis of indazole is mainly due to the difficulty in constructing the azide fragment in the five-membered ring structure. The classic indazole synthesis method directly uses a hydrazine-containing precursor or reagent to react, such as a hydrazine substrate and an o-fluorophenylcarbonyl substrate undergoing a condensation reaction to obtain an indazole structure (J. Org. Chem. 2006, 71, 8166; Synthesis 1999, 588); an in situ generated benzylene undergoes a condensation reaction with hydrazide imine to obtain an indazole structure (Angew. Chem. Int. Ed. 2007, 46, 3323; Org. Lett. 2011, 13, 3340; Org. Lett. 2010, 12, 3368). However, such methods often require more stringent conditions, such as the preparation of phenylhydrazine from aniline through diazotization or nitrosation, through toxic or unstable hydrazine and diazo compounds, and reacting under strong acid or high temperature conditions, the operation is more complicated and is not conducive to large-scale synthesis.

[0004]

[0005] As an alternative strategy, transition metal-catalyzed CN bond cross-coupling reactions (Adv. Synth. Catal. 2016, 358, 926; Org. Lett. 2007, 9, 525) or intramolecular CH bond functionalization reactions (J. Am. Chem. Soc. 2013, 135, 8802; J. Am. Chem. Soc. 2013, 135, 7122) have become an effective method for constructing indazole building blocks. Although such methods are highly efficient and reliable, they usually only obtain N-substituted indazole structures, and the amount of metal catalyst used is large, and the process cost of removing metal contaminants during product purification is faced, especially in the pharmaceutical industry.

[0006]

[0007] In principle, metal-free processes are preferred, and the development of mild, practical, and more efficient methods is highly desirable. Bolm's group (Angew. Chem. Int. Ed. 2013, 52, 7509) reported a mild, metal-free base-catalyzed CN bond condensation reaction of ortho-haloaryl hydrazine substrates to synthesize indazole structures.

[0008] Although this type of method avoids the use of metal catalysts, it can only produce N-Ts-substituted indazole structures.

[0009]

[0010] In addition, the research groups of Stambuli (Org. Lett. 2008, 10, 1021), Manna (Tetrahedron Lett. 2014, 55, 2480) and Fletcher (Tetrahedron Lett. 2016, 57, 5301; Tetrahedron Lett. 2019, 60, 150929) adopted a different strategy to achieve the formation of N-N bonds through mild electrophilic amination reactions, thereby obtaining indazole building blocks. This type of method requires the functionalization of o-aminophenylcarbonyl substrates to synthesize oximes, and then activates the hydroxyl group through a one-step Mitsulobu reaction or methylsulfonyl chloride, and performs an electrophilic amination reaction under alkaline conditions in one pot. It is worth noting that this type of reaction first requires the pre-functionalization reaction of o-aminobenzophenone substrates to synthesize oximes, which requires multi-step synthesis and condensation reagents, and is less efficient. In addition, the use of the Mitsulobu reaction and MsCl requires anhydrous conditions, which requires high control of reaction conditions.

[0011]

[0012] In summary, the synthesis of indazole and its derivatives has its limitations from the classic traditional synthesis method to the transition metal catalytic synthesis method. The traditional method of synthesizing indazole has harsh reaction conditions, expensive and toxic raw materials, and strict requirements on water and oxygen content; the metal catalytic method faces cost pressure caused by the removal of metal pollutants; although a series of other optional indazole structure synthesis methods have been developed, the development of a faster, more efficient, mild, simple, and metal-free synthesis method undoubtedly has more important research significance and industrial application prospects. Summary of the invention:

[0013] The technical problem to be solved by the present invention is to provide a method for preparing an indazole molecular building block, with mild reaction conditions, easy product purification and high process safety; and the method is applied to the synthesis of drugs containing indazole structures, which can greatly simplify the synthesis steps of these drugs and reduce costs.

[0014] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0015] One of the purposes of the present invention is to provide a method for preparing an indazole molecular building block, using o-carbonylaniline as a raw material and reacting it with a Boc-protected hydroxylamine derivative LgONHBoc or a hydroxylamine derivative LgONH2 to obtain an indazole molecular building block.

[0016] The reaction equation is as follows:

[0017]

[0018] Wherein, Ar is an aromatic hydrocarbon or a heterocyclic aromatic hydrocarbon;

[0019] R 1 is H, alkane, alkene, sodium or potassium carboxylate, aromatic hydrocarbon or heteroaromatic hydrocarbon;

[0020] R is H, alkane or aromatic hydrocarbon;

[0021] Lg is a benzoyl group, a substituted benzoyl group, an aryl-substituted sulfonyl group, an alkyl-substituted sulfonyl group or a sulfonic acid group.

[0022] Preferably, the substituted benzoyl group is a benzoyl group substituted with an electron-withdrawing group, including pentafluorobenzoyl, p-nitrobenzoyl, and the like.

[0023] Preferably, the aryl-substituted sulfonyl group includes p-toluenesulfonyl, 2,4,6-trimethylbenzenesulfonyl and the like.

[0024] Preferably, the alkyl-substituted sulfonyl group includes methylsulfonyl and the like.

[0025] Preferably, the molar ratio of o-carbonylaniline to LgONHBoc or LgONH2 is 1:(1.5-2.0).

[0026] Preferably, the solvent of the reaction is trifluoroethanol, hexafluoroisopropanol, methanol / acetic acid (1-5% v / v), methanol / methanesulfonic acid (1-5% v / v), methanol / trifluoroacetic acid (1-5% v / v), etc., to form a weakly acidic reaction system.

[0027] Preferably, the reaction temperature is 45-60°C.

[0028] The preparation principle of the indazole molecular building block of the present invention:

[0029] o-Carboxylaniline and the Boc-protected hydroxylamine derivative LgONHBoc or the hydroxylamine derivative LgONH2 first undergo a condensation reaction to form an oxime, and then rapidly undergo an intramolecular electrophilic amination reaction to obtain an indazole skeleton.

[0030] The second object of the present invention is to provide the application of the preparation method of the aforementioned indazole molecular building block in drug synthesis.

[0031] The drugs are drugs containing indazole structures, including axitinib, granisetron, lonidamine, 4-(1-benzyl-1H-indazole-3-yl) ethyl benzoate (YD-3), and the like.

[0032] The beneficial effects of the present invention are:

[0033] (1) The raw materials used in the present invention are all industrial raw materials and are easily available; there is no metal catalytic reaction, which is safe and reliable; the by-products can be removed by simple alkali washing, the product is easy to purify, and the yield is stable.

[0034] (2) The present invention adopts a weakly acidic reaction system with mild conditions, is insensitive to water and air, and has a yield of 80-97%, which is suitable for industrial production. Description of the drawings:

[0035] Figure 1 This is the H NMR spectrum of 3-methyl-1H-indazole synthesized in Example 1;

[0036] Figure 2 This is the H NMR spectrum of 1,3-dimethyl-1H-indazole synthesized in Example 17;

[0037] Figure 3 This is the H NMR spectrum of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) synthesized in Example 22;

[0038] Figure 4 This is the H NMR spectrum of axitinib synthesized in Example 23. Specific implementation method:

[0039] 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 described below in conjunction with specific embodiments.

[0040] Example 1

[0041] Synthesis of 3-methyl-1H-indazole:

[0042]

[0043] 0.2 mmol of o-aminoacetophenone was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 hours. Then, the solvent was removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 94%. 1H NMR (400MHz, CDCl3) δ10.69(s,1H),7.69(d,J=8.1Hz,1H),7.44(d,J=8.3Hz,1H),7.37(t,J=7.5Hz,1H),7.14(t,J=7.4Hz,1H),2.63(s,3H).

[0044] Example 2

[0045] Synthesis of 3-ethyl-1H-indazole:

[0046]

[0047] 0.2 mmol of 1-(2-amino-phenyl)-propane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then the solvent was removed under low pressure, the by-products were removed by alkali washing, the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.72(d,J=8.1Hz,1H),7.43(d,J=8.4Hz,1H),7.38–7.31(m,1H),7.17–7.08(m,1H),3.04–2.98(m,1H),1.67(d,J=7.4Hz,6H).

[0048] Example 3

[0049] Synthesis of 1H-indazole-3-carboxylic acid:

[0050]

[0051] 0.2 mmol of 1-(2-aminophenyl)carboxylic acid-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 94%. 1 H NMR (400MHz, CDCl3) δ10.58(s,1H),7.83(d,J=8.1Hz,1H),7.56(d,J=8.3Hz,1H),7.44(t,J=7.5Hz,1H),7.30(t,J=7.4Hz,1H).

[0052] Example 4

[0053] Synthesis of 3-(but-3-en-1-yl)-1H-indazole:

[0054]

[0055] 0.2 mmol of 1-(2-aminophenyl)-4-penten-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. The solvent was then removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 83%. 1 H NMR (400MHz, CDCl3) δ7.72(d,J=8.1Hz,1H),7.43(d,J=8.4Hz,1H),7.38–7.31(m,1H),7.17 –7.08(m,1H),6.42–6.40(m,1H),6.22–6.18(m,2H),2.98–2.96(m,2H),2.13–2.07(m,2H).

[0056] Example 5

[0057] Synthesis of 3-(naphthalene-1-yl)-1H-indazole:

[0058]

[0059] 0.2 mmol of 1-naphthyl-2-aminophenyl-methanone was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then the solvent was removed under low pressure, the by-products were removed by alkali washing, the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 75%. 1 H NMR (300MHz, C2D6SO) δ13.43(s,1H),8.28(d,J=7.8Hz,1H),8.04(d,J=7.7Hz,2H),7.78(d ,J=6.2Hz,1H),7.69–7.61(m,3H),7.58–7.49(m,2H),7.46(s,1H),7.18(d,J=6.8Hz,1H).

[0060] Example 6

[0061] Synthesis of 3-(pyridin-2-yl)-1H-indazole:

[0062]

[0063] 0.2 mmol of 2-(2-aminobenzoyl)pyridine was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 89%. 1H NMR (400MHz, CDCl3) δ10.55(s,1H),9.27(d,J=1.0Hz,1H),8.70-8.68(m,1H),8.29(dt,J=7.9, 1.7Hz,1H),8.03(d,J=8.2Hz,1H),7.56(m,1H),7.48-7.45(m,2H),7.31-7.26(t,J=7.4Hz,1H).

[0064] Example 7

[0065] Synthesis of (E)-3-phenylvinyl-1H-indazole:

[0066]

[0067] 0.2 mmol (E)-1-(2-aminophenyl)-3-phenylprop-2-en-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 hours. Then, the solvent was removed under low pressure, the by-products were removed by alkali washing, the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 86%. 1 H NMR(400MHz, CDCl3)δ12.05(bs,1H),8.03-8.07(m,3H),7.55-7.59(m,2H),7.48-7.50(m,1H),7.33- 7.36(m,1H),7.21-7.24(m,1H),7.17(d,J=8.4,1H),6.98(d,J=10.1Hz,1H),6.95(d,J=10.2Hz,1H).

[0068] Example 8

[0069] Synthesis of 3,6-dimethyl-1H-indazole:

[0070]

[0071] 0.2 mmol of 1-(2-amino-4-methylphenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ7.58(d,J=4.8Hz,1H),7.22(s,1H),7.58(d,J=4.8Hz,1H),2.64(s,3H),2.44(s,3H).

[0072] Example 9

[0073] Synthesis of 6-bromo-3-methyl-1H-indazole:

[0074]

[0075] 0.2 mmol of 1-(2-amino-4-bromophenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, the by-products were removed by alkali washing, and the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 79%. 1 HNMR (400MHz, CDCl3) δ7.78 (s, 1H), 7.60 (d, J = 4.8Hz, 1H), 7.20 (d, J = 4.8Hz, 1H), 2.69 (s, 3H).

[0076] Example 10

[0077] Synthesis of 5-bromo-3-methyl-1H-indazole:

[0078]

[0079] 0.2 mmol of 1-(2-amino-5-bromophenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, the by-products were removed by alkali washing, and the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 83%. 1 HNMR (300MHz, CDCl3) δ7.79 (d, J = 2Hz, 1H), 7.43 (dd, J = 9.2Hz, 1H), 7.21 (d, J = 9Hz, 1H), 3.98 (s, 3H), 2.53 (s, 3H).

[0080] Embodiment 11

[0081] Synthesis of 5-chloro-3-methyl-1H-indazole:

[0082]

[0083] 0.2 mmol of 1-(2-amino-5-chlorophenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, the by-products were removed by alkali washing, and the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 86%. 1HNMR (300MHz, CDCl3) δ7.66 (d, J = 2Hz, 1H), 7.37 (dd, J = 8.8Hz, 1H), 7.16 (d, J = 9Hz, 1H), 2.53 (s, 3H).

[0084] Example 12

[0085] Synthesis of 5-fluoro-3-methyl-1H-indazole:

[0086]

[0087] 0.2 mmol of 1-(2-amino-5-fluorophenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. The solvent was then removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 91%. 1 HNMR (400MHz, CDCl3) δ10.94(s,1H),7.37(dd,J=9.0,4.1Hz,1H),7.29(dd,J=8.6,2.2Hz,1H),7.15(td,J=8.9,2.3Hz,1H),2.59(s,3H).

[0088] Embodiment 13

[0089] Synthesis of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-indazole:

[0090]

[0091] 0.2 mmol of 1-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 hours. Then, the solvent was removed under low pressure, the by-products were removed by alkali washing, the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 90%. 1 H NMR (300MHz, CDCl3) δ7.42 (d, J = 2Hz, 1H), 7.28 (dd, J = 8.6Hz, 1H), 7.12 (d, J = 8.8Hz, 1H), 2.53 (s, 3H), 1.42 (s, 12H).

[0092] Embodiment 14

[0093] Synthesis of 5-bromo-3-phenyl-1H-indazole:

[0094]

[0095] 0.2 mmol (2-amino-5-bromophenyl)(phenyl)methanone was dissolved in hexafluoroisopropanol, and 0.3 mmol N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then the solvent was removed under low pressure, the by-products were removed by alkali washing, the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 87%. 1 HNMR (400MHz, CDCl3) δ11.89(s,1H),8.13(s,1H),7.94(d,J=7.5Hz,2H),7.51(dt,J=29.0,7.0Hz,4H),7.39(s,1H),7.02(d,J=8.7Hz,1H).

[0096] Embodiment 15

[0097] Synthesis of 5,7-dibromo-3-methyl-1H-indazole:

[0098]

[0099] 0.2 mmol of 1-(2-amino-3,5-dibromophenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 hours. Then, the solvent was removed under low pressure, the by-products were removed by alkali washing, and the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 75%. 1 H NMR (300MHz, CDCl3) δ8.06(s,1H),7.85(s,1H),2.56(s,3H).

[0100] Example 16

[0101] Synthesis of 3-methyl-5-phenyl-1H-indazole:

[0102]

[0103] 0.2 mmol of 1-(4-amino-[1,1'-biphenyl]-3-yl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 hours. Then, the solvent was removed under low pressure, the by-products were removed by alkali washing, and the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 88%. 1 H NMR (300MHz, CDCl3) δ7.98(s,1H),7.90-7.86(m,2H),7.64-7.57(m,2H),7.46-7.36(m,4H),2.56(s,3H).

[0104] Embodiment 17

[0105] Synthesis of 1,3-dimethyl-1H-indazole:

[0106]

[0107] 0.2 mmol of 1-(2-(methylamino)phenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 96%. 1 H NMR (400MHz, CDCl3) δ7.65 (d, J = 8.1Hz, 1H), 7.41–7.29 (m, 2H), 7.17–7.06 (m, 1H), 4.00 (s, 3H), 2.57 (s, 3H).

[0108] Embodiment 18

[0109] Synthesis of 1-isopropyl-3-methyl-1H-indazole:

[0110]

[0111] 0.2 mmol of 1-(2-(isopropylamino)phenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 97%. 1 H NMR (400MHz, CDCl3) δ7.64 (d, J = 8.1 Hz, 1H), 7.34 (ddd, J = 10.7, 9.2, 4.5 Hz, 2H), 7. 14–7.03(m,1H),4.78(dq,J=13.4,6.7Hz,1H),2.58(s,3H),1.57(d,J=6.7Hz,6H).

[0112] Embodiment 19

[0113] Synthesis of 3-methyl-1-phenyl-1H-indazole:

[0114]

[0115] 0.2 mmol of 1-(2-(phenylamino)phenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, the by-products were removed by alkali washing, and the organic phase was collected and dried by spin drying, and recrystallized to obtain the product with a yield of 66%. 1 H NMR (400MHz, CDCl3) δ7.72 (ddd, J=7.4, 4.2, 0.9Hz, 4H), 7.51 (t, J=7.9Hz, 2H) ,7.45–7.38(m,1H),7.32(t,J=7.4Hz,1H),7.20(t,J=7.4Hz,1H),2.66(s,3H).

[0116] Embodiment 20

[0117] Synthesis of 1-benzyl-3-methyl-1H-indazole:

[0118]

[0119] 0.2 mmol of 1-(2-(benzylamino)phenyl)ethane-1-one was dissolved in hexafluoroisopropanol, and 0.3 mmol of N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 63%. 1 HNMR (300MHz, CDCl3) δ7.84-7.80(m,2H),7.68-7.62(m,2H),7.32-7.29(m,1H),7.20-7.16(m,2H),7.08-7.06(m,2H),5.54(s,2H),2.60(s,3H).

[0120] Embodiment 21

[0121] Synthesis of 5-(trifluoromethyl)-1H-indazole:

[0122]

[0123] 0.2 mmol of 2-amino-5-trifluoromethylbenzaldehyde was dissolved in hexafluoroisopropanol, and 0.3 mmol of hydroxylamine-O-sulfonic acid was added while stirring, and the mixture was reacted at 45°C for 15 h. Then, the solvent was removed under low pressure, and the by-products were removed by alkali washing. The organic phase was collected and dried by spin drying, and then recrystallized to obtain the product with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ8.24 (s, 1H), 7.36 (d, J = 8.4Hz, 2H), 6.72 (d, J = 8.3Hz, 1H), 5.84 (s, 1H).19 F NMR (376MHz,CDCl3)δ-61.26.

[0124] Embodiment 22

[0125] Synthesis of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3):

[0126]

[0127] 1mmol of 2-amino-4'-bromobenzophenone was dissolved in hexafluoroisopropanol, and 1.5mmol of N-Boc-2,4,6-trimethylbenzenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 50°C for 15h to obtain 3-(4-bromophenyl)-1H-indazole (yield 91%); then 3-(4-bromophenyl)-1H-indazole was dissolved in dimethylformamide, and 1.5mmol of benzyl bromide and 1.5mmol of potassium carbonate were added, and the mixture was stirred at 45°C overnight to obtain 1-benzyl-3-(4-bromophenyl)-1H-indazole (yield 83%); then 1-benzyl-3-(4-bromophenyl)-1H-indazole was dissolved in toluene, and CO and EtOH were added, and the mixture was stirred overnight under the catalysis of [Pd(allyl)Cl]2 to obtain YC-3. 1 H NMR (400MHz, DMSO-d6) δ8.16 (dd, J=8.0, 6.0Hz, 3H), 8.10 (d, J=8.4Hz, 2H), 7.81 (d, J=8.4Hz, 1H) ,7.44–7.48(m,1H), 7.23–7.33(m,6H),5.77(s,2H),4.34(q,J=7.2Hz,2H),1.34(t,J=7.2Hz,3H).

[0128] Embodiment 23

[0129] Synthesis of Axitinib:

[0130]

[0131] 1.0mmol 1-(2-amino-4-bromophenyl)ethanone was dissolved in ethanol, 1.0mmol 2-pyridinecarboxaldehyde was added under alkaline conditions, and the mixture was stirred at 0°C to room temperature overnight to obtain intermediate 1 (yield 92%); intermediate 1 was then dissolved in hexafluoroisopropanol, 1.5mmol N-Boc-O-toluenesulfonylhydroxylamine was added while stirring, and the mixture was reacted at 45°C for 15h to obtain intermediate 2 (yield 76%); 3.0mmol anhydrous ethanol and 0.6mL Et3N were added to a mixture of 0.2mmol intermediate 2, 0.22mmol benzoic acid dimethylamide-2-thiophenol, 0.02mmol palladium acetate and 0.02mmol XantPhos, a CO balloon (1-2atm) was added, the mixture was reacted at 70°C for 24h, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and purified by column chromatography to obtain axitinib. 1 HNMR(400MHz, DMSO-d6)δ2.78(d,J=4.4Hz,3H),7.05(d,J=7.6Hz,1H),7.19(d,J= 8.8Hz,1H),7.25–7.34(m,3H),7.50(dd,J=7.2,1.6Hz,1H),7.58(d,J=16.4Hz,1H ),7.61(s,1H),7.66(d,J=8.0Hz,1H),7.78–7.83(m,1H),7.96(d,J=16.4Hz,1H), 8.21(d,J=8.8Hz,1H),8.39(q,J=4.8Hz,1H),8.60(d,J=4.0Hz,1H),13.36(s,1H).

[0132] Compared with the disclosed axitinib synthesis method, the present invention can simplify the synthesis process of axitinib to three steps, and the raw materials are easily available, the reaction conditions are mild, and it is easy to industrialize production.

[0133] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing an indazole molecular building block, characterized in that: Taking o-carbonylaniline as raw material, it reacts with Boc-protected hydroxylamine derivative LgONHBoc or hydroxylamine derivative LgONH2 to obtain indazole molecular building blocks; The reaction equation is as follows: Wherein, Ar is an aromatic hydrocarbon or a heterocyclic aromatic hydrocarbon; R 1 is H, alkane, alkene, sodium or potassium carboxylate, aromatic hydrocarbon or heteroaromatic hydrocarbon; R is H, alkane or aromatic hydrocarbon; Lg is an aryl-substituted sulfonyl group, an alkyl-substituted sulfonyl group or a sulfonic acid group; The solvent of the reaction is hexafluoroisopropanol; The reaction temperature is 45-60°C.

2. The method for preparing the indazole molecular building block according to claim 1, characterized in that: The aryl-substituted sulfonyl group is p-toluenesulfonyl or 2,4,6-trimethylbenzenesulfonyl.

3. The method for preparing the indazole molecular building block according to claim 1, characterized in that: The alkyl-substituted sulfonyl group includes a methylsulfonyl group.

4. The method for preparing the indazole molecular building block according to claim 1, characterized in that: The molar ratio of the o-carbonylaniline to LgONHBoc or LgONH2 is 1:(1.5-2.0).

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