Disclosure of Invention
In order to solve the defects in the prior art, the technical scheme provided by the invention is as follows:
First, the present invention provides a compound of formula (I), having the structural formula:
,
Wherein:
a is a 4-7 membered unsaturated heterocyclic ring containing 1-2 hetero atoms N, O;
n is an integer of 1 to 6;
R1 is a substituent group comprising H or alkyl, alkoxy, wherein the alkyl can be methyl, ethyl, propyl, isopropyl;
Q is each independently HR3 or R2,R3 and R2 may be one or more-CH2-C1-6 alkyl, -CH2-C1-6 alkoxy, halo-CH2-C1-6 alkyl.
When Q is defined as HR3 in the above compounds of formula (I), the compound of formula (l) has the structure of formula (Ia):
,
When Q is defined as R2 in the above compound of formula (I) and is one or more-CH2-C1-6 alkyl groups, the compound of formula (I) has the structure of formula (Ib):
,
wherein A is 5-membered unsaturated heterocycle containing 1-2 hetero atoms N, O;
n, p is an integer of 1 to 2;
r1 is H or alkyl.
In a preferred embodiment of the present invention, A is preferably a 5-to 6-membered unsaturated heterocyclic ring containing 1 to 2 hetero atoms N, O, more preferably a 5-membered unsaturated heterocyclic ring containing 1 to 2 hetero atoms N, O, still more preferably A is the following group:
,,,, . Wherein, the two left side connection bonds of the preferable group A are connected with benzene rings adjacent to A in the structure of the formula (I), and actually form the structure of A and benzene rings. The bond on the right side or lower side of the A group is connected with the structural formula (I)A group.
N is preferably an integer of 1 to 3, more preferably an integer of 1 to 2.
R1 is preferably H or alkyl, preferably H.
Q is preferably HR3 or R2,R3 and R2 is preferably 1 or more-CH2-C1-6 alkyl, -CH2-C1-6 alkoxy, halo-CH2-C1-6 alkyl, more preferably 1 to 2 CH2-C1-3 alkyl, -CH2-C1-3 alkoxy, still more preferably 1 to 2-CH2-C1-3 alkyl, still more preferably 1 to 2-CH2-C1-3 alkyl.
The present invention provides the following preferred compounds of formula (I), in particular:
,,。
Further, the compound of the general formula (I) provided by the invention can be prepared by a synthetic method shown in the following, wherein the method comprises the steps of preparing the compound of the formula (II) through a reduction reaction of the compound of the formula (III), and preparing the compound of the general formula (I) through a continuous substitution reaction of the compound of the formula (II), wherein the reaction equation is as follows:
wherein, A, n, R1, Q are defined as above.
The preparation method further comprises the following reaction equation,
,
Wherein A is a 5-membered unsaturated heterocyclic ring containing 2 heteroatoms N;
n is 1, R1 is H, R3 and R2 are 1 or more-CH2-C1-6 alkyl groups.
Or a reaction equation as follows,
Wherein A is a 5-membered unsaturated heterocyclic ring containing 2 heteroatoms N, N, p is 1, and R1 is H.
A preferred embodiment of the present invention is:
,
or as shown in the following,
。
The invention provides a preparation method for synthesizing N, N-diisobutyl-1H-indazole-4-amine (a 5) and an intermediate thereof, and more preferably an embodiment has the following general reaction equation:
。
The specific implementation mode is that the method I comprises the steps of preparing the compound (A5-1) by continuous substitution reaction of the compound (A3-1) in a solvent under alkaline conditions, the method II comprises the steps of preparing the compound (A3-2) by reduction reaction of the compound (A2-2) in an acidic environment in the presence of a reducing agent, preparing the compound (A4-2) by halogenated hydrocarbon substitution of the compound (A3-2), and preparing the compound (A5-2) by halogenated hydrocarbon substitution of the compound (A4-2).
In some embodiments, the compound (A3-1) or the compound (A2-2) referred to in the above methods one and two can be prepared from the compound A. The compound N, N-diisobutyl-1H-indazol-4-amine can be prepared from intermediate (A5-1) or intermediate (A5-2).
In the method of the present invention, the first method is a nucleophilic substitution reaction. The base may be one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including monobasic potassium phosphate, dibasic potassium phosphate and tribasic potassium phosphate), sodium phosphate (including monobasic sodium phosphate, dibasic sodium phosphate and tribasic sodium phosphate), preferably potassium carbonate. The base may be 1.0 to 1.3 eq, preferably 1.0 to 1.1 eq, preferably 1.05 eq. The reaction may be carried out in the presence of one or more solvents selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether, dimethyl sulfoxide. Preferably, the solvent may be N, N-dimethylformamide, tetrahydrofuran or dichloromethane. More preferably, the solvent may be N, N-dimethylformamide.
In the method of the present invention, the reaction step (i) in the second method is a reduction reaction. The reducing agent can be iron powder, zinc powder, preferably iron powder. The acidic condition may be ammonium chloride, hydrochloric acid, sulfuric acid, preferably ammonium chloride. The iron powder is used in an amount of 1.0-2.5 eq, preferably 1.7 eq eq. The solvent is selected from tetrahydrofuran, hexamethylphosphoramide, C1-C5 alcohol, dimethyl ether, diethyl ether, diisopropyl ether, ethyl acetate, dimethoxyethane and toluene. Preferably, the solvent may be water, tetrahydrofuran or a C1-C5 alcohol (such as methanol, ethanol, propanol, isopropanol, butanol, etc.). More preferably, the solvent may be a mixed solvent of ethanol and water in a ratio of 5:1, 4:1, 1:2, preferably 4:1.
In the process of the present invention, the reaction step (ii) in the second process is a substitution reaction. The base may be one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including monobasic potassium phosphate, dibasic potassium phosphate and tribasic potassium phosphate), sodium phosphate (including monobasic sodium phosphate, dibasic sodium phosphate and tribasic sodium phosphate), preferably potassium carbonate. The base may be 1.0 to 1.3 eq, preferably 1.0 to 1.1 eq, preferably 1.05 eq. The reaction solvent is selected from N, N-dimethylformamide, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether and dimethyl sulfoxide. Preferably, the solvent may be N, N-dimethylformamide, tetrahydrofuran or dichloromethane. More preferably, the solvent may be N, N-dimethylformamide.
In the method of the present invention, the reaction step (iii) in the method II is a substitution reaction. The base may be any one of lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium hydride, preferably lithium bis (trimethylsilyl) amide. The base may be 1.0 to 1.3 eq, preferably 1.0 to 1.1 eq, preferably 1.05 eq. The solvent for the reaction is selected from tetrahydrofuran, toluene, dimethyl ether, diethyl ether and diisopropyl ether. Preferably, the solvent may be tetrahydrofuran or dimethyl ether. More preferably, the solvent is tetrahydrofuran.
In the method of the present invention, the compound (A3-1) or the compound (A2-2) is produced from the compound (A) in a solvent under basic conditions. The base may be one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including monobasic potassium phosphate, dibasic potassium phosphate and tribasic potassium phosphate), sodium phosphate (including monobasic sodium phosphate, dibasic sodium phosphate and tribasic sodium phosphate), preferably potassium carbonate. The reaction solvent is selected from N, N-dimethylformamide, tetrahydrofuran, dichloromethane, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether and dimethyl sulfoxide. Preferably, the solvent may be N, N-dimethylformamide, tetrahydrofuran or dichloromethane. More preferably, the solvent may be N, N-dimethylformamide.
In the process of the present invention, the compound N, N-diisobutyl-1H-indazol-4-amine is prepared from intermediate (A5-1) or intermediate (A5-2) in a solvent under basic conditions. The alkalinity may be one of potassium tert-butoxide, sodium hydride, preferably potassium tert-butoxide. The reaction may be carried out in the presence of one or more solvents selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, hexamethylphosphoramide, dimethyl ether, dimethyl sulfoxide. Preferably, the solvent may be N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide. More preferably, the solvent may be tetrahydrofuran, dimethyl sulfoxide.
Compared with the prior art, the invention has the beneficial effects that the intermediate of the compound N, N-diisobutyl-1H-indazole-4-amine and the novel preparation method are prepared by taking the 4-nitro-1-H-indazole as a reaction raw material and introducing a benzyl protecting group, then carrying out reduction reaction, continuous substitution and debenzylation reaction, the method improves the total reaction yield to 23 percent, the process is simple to operate, the reaction condition is mild, the byproducts are few, the universality of the substrate is high, and the economic benefit is higher,
Detailed Description
The following detailed description of the preferred embodiments of the invention is provided to enable those skilled in the art to more readily understand the advantages and features of the invention and to make a clear and concise definition of the scope of the invention.
Example 1
Adding a compound A (9.95 g,61 mmol) and potassium carbonate (16.86 g,122 mmol) into a 250mL three-neck round-bottom flask under the condition of 18 ℃ and nitrogen, rapidly adding ultra-dry N, N-dimethylformamide (120 mL), dissolving and stirring, dropwise adding bromobenzyl (11.48 g,67 mmol) after 10 minutes, reacting for 17 hours, detecting a sampling point plate, indicating that the raw materials disappear, generating target products, having more impurity points, adding 300 mL water for quenching and stirring, extracting 3 times (50 mL of x 3) with a large amount of water and ethyl acetate, collecting an organic phase, washing 3 times with a large amount of saline solution, collecting the organic phase, drying with anhydrous sodium sulfate, spinning the filtrate at 43 ℃ to obtain black solid, adding ethyl acetate for dissolving, adding a proper amount of silica gel powder, spinning to be powdery, dry-loading, collecting two products by the points respectively with N-hexane for leaching solution, and obtaining a golden yellow solid compound A2-1（7.43 g,48.1%）.1H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.34 – 7.29 (m, 3H), 7.21 – 7.19 (m, 2H), 5.69 (s, 2H). to obtain an orange solid compound A2-2（6.95 g,45.0%）.1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.43-7.35 (m, 6H), 5.68 (s, 2H).
Example 2
Weighing compound A2-1 (7.43 g,29.3 mmol), iron powder (16.4 g,293 mmol) and ammonium chloride (785 mg,14.7 mmol) in a 500 mL three-neck flask at 24deg.C (room temperature), adding 196 mL ethanol and 49 mL water under nitrogen, stirring, transferring to a 98 deg.C oil bath for heating reflux for 1 hr, sampling, quenching with potassium carbonate solution, extracting with ethyl acetate to obtain the target product, removing the oil bath for cooling, filtering with funnel and silica gel, washing with ethanol, collecting filtrate, removing ethanol by steaming under reduced pressure at 50deg.C, dissolving with ethyl acetate and adding potassium carbonate solution to adjust pH=8, extracting, washing with ethyl acetate for 3 times (75 mL×3), collecting organic phase, drying with saturated salt for 1 time, collecting organic phase, drying with anhydrous sodium sulfate under reduced pressure, steaming under 43 deg.C to obtain coarse orange solid compound A3-1（6.41 g,98%）.1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 1.0 Hz, 1H), 7.30 – 7.26 (m, 3H), 7.20 – 7.18 (m, 2H), 7.15 – 7.11 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 7.4 Hz, 1H), 5.54 (s, 2H), 4.15-4.10 (m, 2H).
Weighing A2-2 (6.95 g,27.5 mmol), iron powder (15.18 g,275 mmol) and ammonium chloride (738 mg,13.8 mmol) in a 500 mL three-neck flask at 24 ℃ under nitrogen, adding 164 mL ethanol and 41 mL water, stirring, transferring to a 78 ℃ oil bath, heating and refluxing for 2 hours, sampling, quenching with potassium carbonate solution, extracting with ethyl acetate to obtain a point plate, finding the disappearance of the raw material, generating a target product with more impurities, removing the oil bath for cooling, filtering with a funnel and silica gel, washing with ethanol, collecting filtrate, dissolving with ethyl acetate and adding potassium carbonate solution for pH=8 after 50 ℃ reduced pressure rotary evaporation to remove ethanol, extracting, washing with ethyl acetate for 3 times (75 mL×3), collecting an organic phase, washing with saturated salt for 1 time, collecting organic phase, drying with anhydrous sodium sulfate under reduced pressure, evaporating the organic phase under 43 ℃ to obtain a grey green solid compound A3-2（5.65 g,92%）.1H NMR (400 MHz, Chloroform-d) δ 7.82 (s, 1H), 7.40-7.35 (m, 3H), 7.31-7.29 (m, 2H), 7.21 – 7.19 (m, 1H), 7.12 (dd, J = 8.7, 7.0 Hz, 1H), 6.29 – 6.27 (m, 1H), 5.59 (s, 2H), 3.61 (s, 2H).
Example 3
,
Weighing compound A3-1 (6.41 g,28.7 mmol) and potassium carbonate (11.9 g,86.0 mmol) in a 500 mL three-port bottle at a temperature of 22 ℃ and under nitrogen, adding 65 mL of N, N-dimethylformamide, dissolving and stirring for 10 minutes, slowly adding iodoisobutane (10.5 g,57.4 mmol), transferring to a 130 ℃ oil bath pot, heating and reacting for 12 hours, cooling to the room temperature, sampling and quenching with water, extracting with ethyl acetate, wherein an extraction point plate shows that the raw materials are completely reacted, generating a target product, transferring out of the oil bath pot, cooling to the room temperature, filtering and removing potassium carbonate with a sand core funnel, washing with ethyl acetate, collecting filtrate, extracting with a large amount of water and ethyl acetate for 3 times (50 mL of 3), collecting an organic phase, washing with saturated saline for three times, collecting the organic phase, adding anhydrous sodium sulfate for drying, evaporating the organic phase under reduced pressure at 43 ℃ to obtain a crude product, and separating with a column (ethyl acetate: n-hexane=1:30-1:10), obtaining compound A534 to obtain a light yellow solid of 531-5 m-white compound A （385 mg,4%）.1H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 1.0 Hz, 1H), 7.40 – 7.31 (m, 2H), 7.30 – 7.25 (m, 3H), 7.20 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 7.8 Hz, 1H), 5.54 (s, 2H), 3.38 (d, J = 7.2 Hz, 4H), 2.19 – 2.12 (m, 2H), 0.96 (d, J = 6.6 Hz, 12H).13C NMR (100 MHz, Chloroform-d) δ 144.16, 142.04, 137.12, 133.36, 128.69, 127.66, 127.62, 127.33, 115.46, 103.93, 97.68, 61.56, 52.84, 26.74, 20.46.
,
Weighing compound A3-2 (5.65 g,25.3 mmol) potassium carbonate (13.99 g,101.2 mmol) in a 500 mL three-mouth bottle at the temperature of 22 ℃ under the condition of nitrogen, adding 63 mL of N, N-dimethylformamide, dissolving and stirring for 10 minutes, slowly adding iodoisobutane (18.6 g,101.2 mmol), transferring to a 130 ℃ oil bath pot, heating and reacting for 4 hours, cooling to the room temperature, sampling, quenching by water, extracting by an ethyl acetate extraction point plate until the raw materials are completely reacted, generating a target product, removing the oil bath pot, cooling to the room temperature, filtering by a sand core funnel to remove potassium carbonate, washing by ethyl acetate, collecting filtrate, extracting 3 times (50 mL of 3), collecting an organic phase, washing three times by saturated saline, collecting the organic phase, adding anhydrous sodium sulfate, drying, evaporating the organic phase under reduced pressure at 43 ℃ in a rotary manner to obtain a crude product, and separating by a column (ethyl acetate: n-hexane=1:30:1:5) to obtain compound A4-2 m white solid （2.97 g,42%）.1H NMR (400 MHz, Chloroform-d) δ7.78 (s, 1H), 7.35 – 7.30 (m, 3H), 7.26 – 7.24 (m, 2H), 7.17-7.13 (m, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.07 (d, J = 7.1 Hz, 1H), 5.52 (s, 2H), 3.90 (s, 1H), 3.03 (d, J = 6.8 Hz, 2H), 1.95 (dp, J = 13.4, 6.7 Hz, 1H), 1.00 (d, J = 6.7 Hz, 6H).13C NMR (100 MHz, Chloroform-d) δ 150.14, 141.28, 135.99, 128.92, 128.32, 127.98, 127.74, 120.02, 115.16, 106.11, 97.92, 57.36, 51.72, 27.99, 20.64. to obtain compound A4-2 as red solid （1.23 g,14.5%）.1H NMR (400 MHz, Chloroform-d) δ7.86 (s, 1H), 7.37 – 7.27 (m, 5H), 7.14 – 7.13 (m, 2H), 6.23 – 6.18 (m, 1H), 5.55 (s, 2H), 3.16 (d, J = 7.2 Hz, 4H), 2.04 – 1.97 (m, 2H), 0.85 (d, J = 6.7 Hz, 12H).13C NMR (100 MHz, Chloroform-d) δ 151.22, 143.58, 135.93, 128.93, 128.32, 128.03, 127.10, 122.83, 116.34, 106.99, 104.51, 61.24, 57.31, 26.70, 20.56.
Example 4
Transferring the compound A4-1 (4.24 g,15.18 mmol) into a 250 mL three-port reaction bottle under the condition of 18 ℃ and room temperature under the protection of nitrogen, stirring and dissolving, dropwise adding lithium bis (trimethylsilyl) amide (45.5 ml,1 mL/L) at 18 ℃, stirring for 1 hour, slowly adding iodized isobutane (3.52 mL,30.4 mmol), stirring for 1 hour, taking out a sampling point plate to show that the raw materials are not reacted completely (the extension time does not change, generating a target product, stopping the reaction, adding water for quenching, extracting 3 times with water and ethyl acetate (50 mL x 3), merging the organic phases, washing with saturated salt once, adding anhydrous sodium sulfate for drying, and carrying out reduced pressure rotary evaporation on the organic phases at 43 ℃ to obtain a crude product, and separating by a column (ethyl acetate: n-hexane=1:20-1:5). The starting beige solid compound A4-1 was recovered to give the liquid compound A5-1 (2.14 g, 42%) as a yellow oil.
Transferring compound A4-2 (2.97 g,10.6 mmol) into a 250 mL three-port reaction bottle with tetrahydrofuran (32 mL) under the protection of nitrogen at the temperature of 18 ℃ and stirring for dissolution, dropwise adding lithium bis (trimethylsilyl) amide (21.2 mL,1 mOL/L) at the temperature of 18 ℃ to find that yellow liquid becomes turbid gradually, slowly adding isobutene iodide (3.7 mL,31.8 mmol) and stirring for 1 hour (the yellow turbid system becomes brown clear liquid), sampling a sampling point plate shows that the raw material is not reacted completely (the product is unchanged, the target product is generated, stopping the reaction, adding water for quenching, extracting 3 times with water and ethyl acetate (50 x 3), combining the organic phases, washing one time with saturated salt, adding anhydrous sodium sulfate for drying, and carrying out reduced pressure evaporation on the organic phases at the temperature of 43 ℃ to obtain a crude product, and separating the crude product by a column (ethyl acetate: normal hexane=1:30:1:5). The beige solid compound A4-2 was recovered to give the compound A5-2 as a yellow oil (1.89 g, 53%).
Example 5
Transferring potassium tert-butoxide (8.43 g,75 mmol) to a 500 mL round bottom flask at 17 ℃ under room temperature, adding dimethyl sulfoxide (15.9 mL) under oxygen protection, adding 59. 59 mL tetrahydrofuran dissolved compound A5-1 (2.52 g,7.5 mmol), stirring for 12 hours, sampling the plates to show no raw material and new product, stopping the reaction, adding saturated sodium chloride aqueous solution 250 mL, extracting with ethyl acetate (4 x 60 mL), merging the organic phases, washing the organic phases with saturated salt once, adding anhydrous sodium sulfate for drying, decompressing and steaming the organic phases under 45 ℃ to obtain a crude product, and separating the crude product by a column (ethyl acetate: n-hexane=1:10-1:5) to obtain a yellow solid compound a5（1.51 g,82%）.1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 1.1 Hz, 1H), 7.28 – 7.22 (m, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 3.37 (d, J = 7.3 Hz, 4H), 2.17 – 2.08 (m, 2H), 0.95 (d, J = 6.7 Hz, 12H).13C NMR (100 MHz, Chloroform-d) δ 144.06, 142.60, 134.73, 128.09, 114.74, 104.47, 98.23, 61.52, 26.73, 20.45.
Example 6
Transferring potassium tert-butoxide (10.44 g,93 mmol) to a 500 mL round bottom flask at 17 ℃ under room temperature, adding dimethyl sulfoxide (19.8 mL) under oxygen protection, adding 72 mL tetrahydrofuran dissolved compound A5-2 (3.12 g,9.3 mmol), stirring for 12 hours, sampling the plates to show no raw material and new product, stopping the reaction, adding saturated sodium chloride aqueous solution 250 mL, extracting with ethyl acetate (4 x 60 mL), merging the organic phases, washing the organic phases with saturated salt once, adding anhydrous sodium sulfate for drying, decompressing and steaming the organic phases at 45 ℃ to obtain a crude product, and separating the crude product by a column (ethyl acetate: n-hexane=1:10-1:5) to obtain a yellow solid compound a5（1.78 g,78%）.1H NMR (400 MHz, Chloroform-d) δ8.16 (s, 1H), 7.29 – 7.22 (m, 1H), 6.85 (d, J = 8.1 Hz,1H), 6.34 (d, J = 7.8 Hz, 1H), 3.38 (d, J = 7.2 Hz, 4H), 2.17 – 2.10 (m, 2H), 0.95 (d, J = 6.6 Hz, 12H).13C NMR (100 MHz, Chloroform-d) δ 144.06, 142.61, 134.72, 128.09, 114.74, 104.45, 98.23, 61.52, 26.73, 20.45.
The foregoing description is only illustrative of the present invention and is not intended to limit the scope of the invention, and all equivalent structures or equivalent processes or direct or indirect application in other related arts are included in the scope of the present invention.