CN114805194A - Continuous hydrogenation method of 2-nitropyridine derivative and application thereof - Google Patents

Continuous hydrogenation method of 2-nitropyridine derivative and application thereof Download PDF

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CN114805194A
CN114805194A CN202210747844.7A CN202210747844A CN114805194A CN 114805194 A CN114805194 A CN 114805194A CN 202210747844 A CN202210747844 A CN 202210747844A CN 114805194 A CN114805194 A CN 114805194A
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郝昆明
骆玉成
秦小飞
周西朋
杨尚彦
龚彦春
刘永强
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Nanjing Weikaier Biomedical Technology Co ltd
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Abstract

The invention provides a continuous hydrogenation method of a 2-nitropyridine derivative, which comprises the following steps: dissolving the 2-nitropyridine derivative (II) in a solvent, and mixing the solution with hydrogen to form a gas-liquid mixture as a reaction raw material; continuously feeding the reaction raw material into a fixed bed reactor to perform catalytic hydrogenation reaction, and continuously discharging the 2-aminopyridine derivative (I). The method can effectively control the reaction state in the reactor, greatly increase the reaction efficiency, reduce the risk of impurity generation, and improve the yield and purity of the target product and the product performance stability. The catalyst after the catalytic hydrogenation reaction does not need to be filtered, the spontaneous combustion risk of the catalyst is reduced, the catalyst does not have the inactivation phenomenon, and the recovered catalyst can also be recycled. The method has the advantages of low cost, high yield and high purity of the 2-aminopyridine derivative (I) and the like.

Description

Continuous hydrogenation method of 2-nitropyridine derivative and application thereof
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a continuous hydrogenation method of a 2-nitropyridine derivative (II) and application thereof.
Background
2-aminopyridine derivatives (I) are important intermediates widely used in the biomedical field, such as Trilaciclib (Trilaciclib), a cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor for the treatment of myelosuppression, small cell lung cancer, approved by FDA on 12/2/2021 in the United states; the us FDA approved the marketed cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor pipariril (Palbociclib) for metastatic breast cancer on day 1/3 of 2015; 1-class innovative drug of dalcill isethionate (Dalpiciclib) developed by Henry pharmaceutical Co., Ltd, Jiangsu, the national drug administration of 12 months 2021 approved dalcil through a priority examination and approval program for recurrent or metastatic breast cancer patients with positive hormone receptors and negative human epidermal growth factor receptor 2, who have disease progression after previous endocrine treatment; in addition, drugs such as Lerociclib developed by G1 therapeutics, Ribociclib developed by Nowa, and the like, all contain a 2-aminopyridine fragment structure.
Figure 959174DEST_PATH_IMAGE001
The existing preparation method of the 2-aminopyridine derivative (I) is generally that the 2-nitropyridine derivative (II) is prepared by batch reduction reaction with a catalyst and hydrogen in a catalytic hydrogenation reduction reactor.
Figure 280434DEST_PATH_IMAGE002
The process has the problems of higher safety requirements on hydrogen and reaction devices, large operation labor amount and high operation requirements of the autoclave, filtering of the catalyst, difficulty in controlling spontaneous combustion of the catalyst, long hydrogenation reaction time, low conversion rate and easiness in generating the azo impurities A and the impurities B.
Figure 831501DEST_PATH_IMAGE003
The existence of the impurity A and the impurity B causes the color of reaction liquid and products to be darker, and further research finds that the impurity A and the impurity B are easy to be separated out together with the product 2-aminopyridine derivative (I) in the crystallization process, are not easy to remove, seriously affect the appearance and the purity of the product, and the color of the product on the market is dark purple, dark brown and the like at present.
In view of the above problems, the present application provides a continuous hydrogenation method of 2-nitropyridine derivative (II).
Disclosure of Invention
The invention mainly aims to provide a continuous hydrogenation method of a 2-nitropyridine derivative (II) and application thereof, and aims to solve the problems of high safety requirements on hydrogen and reaction devices, high autoclave operation labor amount, high operation requirements, filtering requirements on a catalyst, difficulty in controlling spontaneous combustion of the catalyst, long hydrogenation reaction time, low conversion rate, easiness in generating azo impurities A and impurities B and the like in the existing 2-nitropyridine derivative catalytic hydrogenation reaction process.
In order to achieve the above object, one aspect of the present invention provides a continuous hydrogenation method of a 2-nitropyridine derivative (II), the continuous hydrogenation method comprising: dissolving the 2-nitropyridine derivative (II) in a solvent, and mixing the solution with hydrogen to form a gas-liquid mixture as a reaction raw material; continuously feeding the reaction raw materials into a fixed bed reactor for catalytic hydrogenation reaction, and continuously discharging the 2-aminopyridine derivatives (I);
Figure 427567DEST_PATH_IMAGE004
wherein R is 1 、R 2 Each independently selected from H, C 1 - 6 A linear or branched alkyl group; or R 1 、R 2 And N attached thereto may form optionally substituted by one or more R 3 A substituted 4-to 6-membered heterocyclic group;
R 3 selected from H, C 1-6 A linear or branched alkyl, acetyl, tert-butoxycarbonyl or benzyl group;
the gas-liquid ratio of the gas-liquid mixture is 15-50: 1, the reaction temperature is 30-80 ℃, the reaction pressure is 0.5-3 MPa, and the volume space velocity is 1-6 h in the catalytic hydrogenation reaction -1 ；
The fixed bed reactor is filled with a spherical catalyst in a reaction column, and the catalyst is selected from Pt/C, Ru/C or Pd/C.
Furthermore, in order to improve the mass transfer effect between the reaction raw materials and the catalyst, the particle size of the catalyst is 0.1-5 mm.
Further, the bed pressure drop of the fixed bed reactor is less than 0.01 MPa/m.
Further, the fixed bed reactor is selected from an axial adiabatic fixed reaction bed, a radial adiabatic fixed reaction bed or a tubular fixed bed.
Further, the fixed bed reactor is filled with a spherical Pt/C catalyst in a reaction column.
Further, in the catalytic hydrogenation reaction, the reaction temperature is 40-60 ℃, the reaction pressure is 1-2 MPa, and the volume space velocity is 5-6 h -1 。
Further, the solvent is selected from one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran.
Further, the solvent is selected from a mixed solvent of methanol/tetrahydrofuran, methanol/2-methyltetrahydrofuran, ethanol/tetrahydrofuran, and ethanol/2-methyltetrahydrofuran. The weight ratio of methanol or ethanol to tetrahydrofuran or 2-methyltetrahydrofuran is about 1-3: 1, preferably 2: 1.
Further, the mass ratio of the 2-nitropyridine derivative (II) to the solvent is about 4-10: 100, preferably 5-8: 100.
In certain embodiments of the present invention, R of 2-nitropyridine derivative (II) and 2-aminopyridine derivative (I) 1 、R 2 Each independently selected from H, C 1 - 6 Straight or branched chain alkyl.
In certain embodiments of the present invention, R of 2-nitropyridine derivative (II) and 2-aminopyridine derivative (I) 1 、R 2 Each independently selected from H, methyl, ethyl or tert-butyl.
In certain embodiments of the present invention, R of 2-nitropyridine derivative (II) and 2-aminopyridine derivative (I) 1 、R 2 And N attached thereto optionally substituted by one or more R 3 A substituted 4-to 6-membered heterocyclic group.
The 4-to 6-membered heterocyclic group is selected from
Figure 4480DEST_PATH_IMAGE005
Wherein A is selected from C, O or N.
Further, the 4-6 membered heterocyclic group is selected from
Figure 231062DEST_PATH_IMAGE006
。
Further, the 4-6 membered heterocyclic group is selected from
Figure 207109DEST_PATH_IMAGE007
。
Wherein R is 3 Selected from H, C 1-6 A linear or branched alkyl group, an acetyl group, a tert-butoxycarbonyl group, or a benzyl group.
Further, R 3 Selected from H, methyl, ethyl, isopropyl, 2-dimethylpropyl, acetyl, tert-butoxycarbonyl or benzyl.
The invention also provides an application of the continuous hydrogenation method of the 2-nitropyridine derivative (II) in the synthesis of a medicament for treating cancer.
The invention has the beneficial effects that: by applying the technical scheme of the invention, the reaction state in the reactor can be effectively controlled, the reaction efficiency can be greatly increased, the risk of impurity generation is reduced, and the yield, purity and product performance stability of the target product are improved. The catalyst does not need to be filtered after the catalytic hydrogenation reaction, the spontaneous combustion risk of the catalyst is reduced, the catalyst is continuously subjected to catalytic hydrogenation for 10 days, the deactivation phenomenon does not occur after the test, and the recovered catalyst can be recycled. On the basis, the continuous hydrogenation method has the advantages of low cost, high yield and high purity of the 2-aminopyridine derivative (I), and the like.
Compared with batch reaction, the continuous hydrogenation method has the advantages that the reaction raw material amount in unit time is small, the product is discharged in time, and the generation of coupling impurities is avoided, so that the product is mostly light yellow to off-white in color, attractive in appearance and high in purity. The adopted reaction device has small floor area, has great advantages in heat exchange and equipment pressure bearing improvement, and can successfully realize the modularization of the reaction device; this can greatly save equipment investment costs, reduce the occupation of land to greatly reduce the safety risk brought by using a large amount of hydrogen.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"C" in the invention 1 - 6 Straight-chain or branched alkyl "refers to straight-chain alkyl groups and branched-chain-containing alkyl groups comprising 1 to 6 carbon atoms, alkyl refers to saturated aliphatic hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylpropyl, 2-C-, 2, 3-dimethylbutyl group or various branched isomers thereof, and the like.
"Heterocyclyl" as used herein refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent wherein one or more ring atoms are selected from nitrogen, oxygen or heteroatoms of S (O) r (where r is an integer 0, 1, 2), but does not include the ring portion of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. "4-to 6-membered heterocyclic group" means a heterocyclic group containing 4 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention;
FIG. 1 is a schematic view showing the structure of a continuous hydrogenation apparatus for 2-nitropyridine derivative (II) used in an exemplary embodiment according to the present invention: 10-raw material storage tank, 20-hydrogen storage tank, P01-plunger pump, V01-one-way valve, H01-heat exchanger, V02-one-way valve, 30-mixer, 40-fixed bed reactor, 50-gas-liquid separation device, V03-back pressure valve, and 60-product storage tank.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The invention is explained in detail below with reference to the figures and with reference to embodiments.
Example 2-nitropyridine derivative (II) was subjected to catalytic hydrogenation with hydrogen using the apparatus shown in FIG. 1. The specific process comprises the following steps: dissolving the 2-nitropyridine derivative (II) in a solvent and storing the solvent in a raw material storage tank 10; hydrogen gas is stored in the hydrogen storage tank 20. The 2-nitropyridine derivative (II) is preheated by a plunger pump P01, a check valve V01 and a heat exchanger H01, and then mixed with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture. And (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product system. The product system is subjected to gas-liquid separation by a gas-liquid separation device 50, a liquid-phase product is the required target product 2-aminopyridine derivative (I), the product is stored in a product storage tank 60, and a gas phase is discharged after passing through a back pressure valve V03.
Example 1
Figure 278970DEST_PATH_IMAGE008
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-1 in methanol to prepare a solution with the mass concentration of 10%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 30-40 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 50: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-1. Wherein the reaction temperature is 30-40 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 6 h -1 And running for 48 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.6 percent, and the product purity is 99.2 percent; the catalyst utilization (w/w) was 37.
1 H-NMR (400 MHz, CDCl 3 ) δ 2.83 (s, 6H), 4.08 (br s, 2H), 6.49 (m, 1H), 7.08 (m, 1H), 7.67 (m, 1H); MS: M+H + 138。
Example 2
Figure 984758DEST_PATH_IMAGE009
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-2 in ethanol to prepare a solution with the mass concentration of 10%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 40-50 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 40: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-2. Wherein the reaction temperature is 40-50 ℃, the reaction pressure is 2.0 MPa, and the volume space velocity is 6 h -1 Run for 48 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.6 percent, and the product purity is 99.1 percent. The catalyst utilization (w/w) was 37.
Example 3
Figure 178979DEST_PATH_IMAGE010
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-3 in ethyl acetate to prepare a solution with the mass concentration of 8%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 40-50 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 30: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-3. Wherein the reaction temperature is 40-50 ℃, the reaction pressure is 3.0 MPa, and the volume space velocity is 6 h -1 And running for 48 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.5 percent, and the product purity is 99.1 percent. The catalyst utilization (w/w) was 29.
Example 4
Figure 704638DEST_PATH_IMAGE011
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-4 in tetrahydrofuran to prepare a solution with the mass concentration of 8%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 30-40 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 20: 1; the gas-liquid mixture is conveyed to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtainTo product I-4. Wherein the reaction temperature is 30-40 ℃, the reaction pressure is 0.5 MPa, and the volume space velocity is 6 h -1 And running for 48 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.5 percent, and the product purity is 98.5 percent. The catalyst utilization (w/w) was 29.
Example 5
Figure 845769DEST_PATH_IMAGE012
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-5 in tetrahydrofuran to prepare a solution with the mass concentration of 8%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 20: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-5. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 48 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.5 percent, and the product purity is 98.6 percent. The catalyst utilization (w/w) was 29.
1 H-NMR (500 MHz, DMSO-d 6 ) δ 7.35 (d, J=2.9 Hz, 1H), 6.84 (dd, J=8.8, 3.0 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 5.01 (s, 2H), 3.14-3.04 (m, 4H), 1.96-1.84 (m, 4H)。
Example 6
Figure 78167DEST_PATH_IMAGE013
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-6 in tetrahydrofuran to prepare a solution with the mass concentration of 8%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 20: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-6. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 48 h. After separation by the gas-liquid separation device 50, the conversion rate of the raw material is 99.3%, and the product purity is 98.5%. The catalyst utilization (w/w) was 29.
1 H-NMR (400 MHz, CDCl 3 ) δ 1.52-1.54 (m, 2H), 1.69-1.73 (m, 4H), 2.97 (t, 4H, J=5.5), 4.15 (s, 2H), 6.47 (d, 1H, J=9.0), 7.18 (dd, 1H, J=9.0 & 3.0), 7.77 (d, ΙΗ, J=3.0)。
Example 7
Figure 646552DEST_PATH_IMAGE014
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-7 in ethanol/tetrahydrofuran to prepare a solution with the mass concentration of 5%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 20: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-7. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 96 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.6 percent, and the product purity is 98.9 percent. The catalyst utilization (w/w) was 37.
1 H-NMR (400 MHz, CDCl 3 ) δ 2.99 (t, 4H, J=4.5), 3.83 (t, 4H, J=4.5), 4.23 (br s, 2H), 6.47 (d, 1H, J=9.0), 7.13 (dd, 1H, J=9.0 & 3.0), 7.75 (d, IH, J=2.5)。
Example 8
Figure 662437DEST_PATH_IMAGE015
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-8 in methanol/tetrahydrofuran to prepare a solution with the mass concentration of 5%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 20: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-8. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 96 h. After separation by the gas-liquid separation device 50, the conversion rate of the raw material is 99.7%, and the product purity is 99.1%. The catalyst utilization (w/w) was 37.
Example 9
Figure 607259DEST_PATH_IMAGE016
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-9 in methanol/tetrahydrofuran to prepare a solution with the mass concentration of 5%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 25: 1;and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-9. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 96 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.6 percent, and the product purity is 99.2 percent. The catalyst utilization (w/w) was 37.
1 H-NMR (400 MHz, CDCl 3 ) δ 2.33 (s, 3H), 2.56 (t, 4H, J=5.0), 3.05 (t, 4H, J=5.0), 4.17 (br s, 2H), 6.47 (d, 1 H, J=9.0), 7.16 (dd, 1H, J=8.5 & 3.0), 7.77 (d, 1H, J=2.5)。
Example 10
Figure 818798DEST_PATH_IMAGE017
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-10 in methanol/tetrahydrofuran to prepare a solution with the mass concentration of 5%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 25: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-10. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 24 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.6 percent, and the product purity is 99.6 percent. The catalyst utilization (w/w) was 19.
1 H-NMR (400 MHz, CDCl 3 ) δ 1.11 (t, 3H, J=7.5), 2.47 (q, 2H, J=7.5), 2.60 (t, 4H, J=4.5), 3.06 (t, 4H, J=4.5), 4.17 (br s, 2H), 6.47 (d, 1H, J=8.5), 7.17 (dd, 1H, J=8.5 & 2.0), 7.77 (d, 1H, J=2.0)。
Example 11
Figure 823663DEST_PATH_IMAGE018
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-11 in tetrahydrofuran to prepare a solution with the mass concentration of 5%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-80 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 25: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-11. Wherein the reaction temperature is 50-80 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 24 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.4 percent, and the product purity is 99.4 percent. The catalyst utilization (w/w) was 19.
1 H-NMR (400 MHz, CDCl 3 ) δ 1.06 (d, 6H, J=6.44), 2.59-2.75 (m, 5H), 2.97-3.10 (m, 4H), 4.13 (s, 2H), 6.45 (d, 1H, J=8.78), 7.15 (dd, 1H, J=9.08 & 2.93), 7.76 (d, 1H, J=2.93). MS(ESI) 221(M+H) + 。
Example 12
Figure 323914DEST_PATH_IMAGE019
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving a raw material II-12 in methanol/2-methyltetrahydrofuran to prepare a solution with the mass concentration of 5%, and placing the solution in a raw material storage tank 10; the raw material solution is preheated to 50-60 ℃ by a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and reacts with hydrogen in a T shapeMixing in the mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 25: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-12. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 24 h. After separation by the gas-liquid separation device 50, the conversion rate of the raw material is 99.6%, and the product purity is 99.2%. The catalyst utilization (w/w) was 19.
Example 13
Figure 806848DEST_PATH_IMAGE020
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-13 in 2-methyltetrahydrofuran to prepare a solution with the mass concentration of 8%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 25: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-13. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 96 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.7 percent, and the product purity is 98.5 percent. The catalyst utilization (w/w) was 29.
1 H-NMR (400 MHz, CDCl 3 ) δ 2.13 (s, 3H), 2.97 (t, 2H, J=5.0), 3.01 (t, 2H, J=5.0), 3.60 (t, 2H, J=5.0), 3.76 (t, 2H, J=5.0), 4.22 (br s, 2H), 6.49 (d, 1H, J=8.5), 7.17 (dd, 1H, J=8.5 & 3.0), 7.78 (d, 1H, J=3.0)。
Example 14
Figure 341735DEST_PATH_IMAGE021
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-14 in methanol/2-methyltetrahydrofuran to prepare a solution with the mass concentration of 8%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 25: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-14. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 2.0 MPa, and the volume space velocity is 5 h -1 And running for 96 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.2 percent, and the product purity is 99.3 percent. The catalyst utilization (w/w) was 29.
1 H-NMR (400 MHz, CDCl 3 ) δ 1.46 (s, 9H), 2.93 (s, 4H), 3.55 (t, 4H, J=5.0), 4.24(br s, 2H), 6.47 (d, 1Η, J=9.0), 7.15(dd, 1H, J=9.0 & 2.5), 7.75 (d, lH, J=2.5)。
Example 15
Figure 517501DEST_PATH_IMAGE022
The reaction column was packed with 5% Pt/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 31 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-15 in ethanol/2-methyltetrahydrofuran to prepare a solution with the mass concentration of 8%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 25: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-15. Wherein,the reaction temperature is 50-60 ℃, the reaction pressure is 2.0 MPa, and the volume space velocity is 5 h -1 And running for 96 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.3 percent, and the product purity is 99.6 percent. The catalyst utilization (w/w) was 29.
Example 16
Figure 507978DEST_PATH_IMAGE016
The reaction column was packed with 5% Pd/C spherical catalyst, wherein the catalyst packing mass was 2.0 g, packing height was 35 mm, packing diameter was 4.6 mm, and catalyst particle diameter was 1 mm, as a fixed bed reactor 40.
Dissolving the raw material II-9 in methanol/tetrahydrofuran to prepare a solution with the mass concentration of 5%, and placing the solution in a raw material storage tank 10; preheating a raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixture, wherein the gas-liquid ratio of the gas-liquid mixture is 25: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-9. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 120 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.5 percent, and the product purity is 96.8 percent. The catalyst utilization (w/w) was 9.
Example 17
Figure 529024DEST_PATH_IMAGE016
The reaction column was packed with 5% Ru/C spherical catalyst, wherein the catalyst packing mass was 2.5 g, packing height was 33 mm, packing diameter was 4.6 mm, and catalyst particle size was 0.5 mm, as a fixed bed reactor 40.
Dissolving the raw material II-9 in methanol/tetrahydrofuran to prepare a solution with the mass concentration of 5%, and placing the solution in a raw material storage tank 10; preheating the raw material solution to 50-60 ℃ through a plunger pump P01, a one-way valve V01 and a heat exchanger H01, and mixing the raw material solution with hydrogen in a T-shaped mixer 30 to obtain a gas-liquid mixtureThe gas-liquid ratio of the material is 25: 1; and (3) conveying the gas-liquid mixture to a fixed bed reactor 40 for catalytic hydrogenation reaction to obtain a product I-9. Wherein the reaction temperature is 50-60 ℃, the reaction pressure is 1.0 MPa, and the volume space velocity is 5 h -1 And running for 120 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.5 percent, and the product purity is 97.8 percent. The catalyst utilization (w/w) was 9.
Comparative example 1
Figure 324942DEST_PATH_IMAGE012
Reference is made to WO2021092262 specification [00134]The method disclosed in paragraph: placing 486 mg of raw material II-5 and 10 mL of ethanol into a reaction bottle, adding 50 mg of 10% Pd/C, replacing the reaction system with hydrogen for 3 times, stirring at normal temperature for reaction for 4 hours, monitoring the completion of the reaction by TLC, carrying out suction filtration on diatomite, washing a filter cake with 5mL of ethanol, concentrating the filtrate to obtain a product I-5 which is 466 mg of dark brown solid, and obtaining the yield: 92 percent; the catalyst utilization (w/w) was 9.32. 1 H-NMR (500 MHz, DMSO-d 6 ) δ 7.35 (d, J=2.9 Hz, 1H), 6.84 (dd, J=8.8, 3.0 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 5.01 (s, 2H), 3.14-3.04 (m, 4H), 1.96-1.84 (m, 4H)。
Comparative example 2
Figure 999506DEST_PATH_IMAGE016
Reference is made to the methods disclosed in Journal of Medicinal Chemistry (2008), 51(12), 3507-: placing 3.4 g of raw material II-9 and 50 mL of methanol into a reaction kettle, adding 1.7 g of 10% Pd/C, replacing the reaction system with hydrogen for 3 times, then carrying out pressurized stirring reaction at normal temperature for 3 hours, monitoring the reaction by TLC, carrying out suction filtration on kieselguhr, washing a filter cake with 20 mL of methanol, and concentrating the filtrate to obtain a product I-9 which is a dark purple solid 2.6 g, wherein the yield is as follows: 90 percent; the catalyst utilization (w/w) was 1.53. MS (ESI) M/z 193.1 (M +1) + 。
Comparative example 3
Figure 146453DEST_PATH_IMAGE018
With reference to ACS Medicinal Chemistry Letters (2013), 4(7), 647-: placing 294 mg of raw material II-11 and 10 mL of methanol into a reaction bottle, adding 29 mg of 10% Pd/C, replacing the reaction system with hydrogen for 3 times, stirring at normal temperature for reaction for 12 hours, monitoring the reaction by TLC, performing suction filtration on diatomite, washing a filter cake with 5mL of methanol, and concentrating the filtrate to obtain a product I-11 which is 130 mg of gray solid with yield: 50 percent; the catalyst utilization (w/w) was 4.48. 1 H-NMR (400 MHz, CDCl3) δ 1.09 (6H, d, J=6.4 Hz), 2.68 (4H, t, J=5.2 Hz), 2.72 (1H, heptet, J=6.4 Hz), 3.06 (4H, t, J=5.2 Hz), 4.15 (2H, br s), 6.49 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=2.4, 8.8 Hz), 7.78 (1H, d, J=2.4 Hz); MS (ESI) m/z 221 (M+1) + 。

Claims (10)

1. A continuous hydrogenation process of a 2-nitropyridine derivative (II), characterized in that it comprises: dissolving the 2-nitropyridine derivative (II) in a solvent, and mixing the solution with hydrogen to form a gas-liquid mixture as a reaction raw material; continuously feeding the reaction raw materials into a fixed bed reactor for catalytic hydrogenation reaction, and continuously discharging the 2-aminopyridine derivatives (I);
Figure 731330DEST_PATH_IMAGE001
wherein R is 1 、R 2 Each independently selected from H, C 1 - 6 A linear or branched alkyl group; or R 1 、R 2 And N attached thereto may form optionally substituted by one or more R 3 A substituted 4-to 6-membered heterocyclic group;
R 3 selected from H, C 1-6 A linear or branched alkyl, acetyl, tert-butoxycarbonyl or benzyl group;
the gas-liquid ratio of the gas-liquid mixture is 15-50: 1; in the catalytic hydrogenation reaction, the reaction temperature is 30-80 ℃, and the reaction pressure is0.5-3 MPa, and the volume airspeed of 1-6 h -1 ；
The fixed bed reactor is filled with a spherical catalyst in a reaction column, and the catalyst is selected from Pt/C, Ru/C or Pd/C.
2. The continuous hydrogenation process of 2-nitropyridine derivative (II) according to claim 1, characterized in that: the bed pressure drop of the fixed bed reactor is less than 0.01 MPa/m.
3. The continuous hydrogenation process of 2-nitropyridine derivative (II) according to claim 1, characterized in that: the fixed bed reactor is selected from an axial adiabatic fixed reaction bed, a radial adiabatic fixed reaction bed or a tubular fixed bed.
4. The continuous hydrogenation process of 2-nitropyridine derivative (II) according to claim 1, characterized in that: the fixed bed reactor is filled with a spherical Pt/C catalyst in a reaction column.
5. The continuous hydrogenation process of 2-nitropyridine derivative (II) according to claim 1, characterized in that: in the catalytic hydrogenation reaction, the reaction temperature is 40-60 ℃, the reaction pressure is 1-2 MPa, and the volume space velocity is 5-6 h -1 。
6. The continuous hydrogenation process of 2-nitropyridine derivative (II) according to claim 1, characterized in that: the solvent is selected from one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran.
7. The continuous hydrogenation method of 2-nitropyridine derivative (II) according to any of claims 1 to 6, characterized in that: the 4-to 6-membered heterocyclic group is selected from
Figure 884619DEST_PATH_IMAGE002
Wherein A is selected from C, O or N.
8. The continuous hydrogenation process of 2-nitropyridine derivative (II) according to claim 7, characterized in that: the 4-to 6-membered heterocyclic group is selected from
Figure 213969DEST_PATH_IMAGE003
。
9. The continuous hydrogenation process of 2-nitropyridine derivative (II) according to claim 8, characterized in that: the 4-to 6-membered heterocyclic group is selected from
Figure 209607DEST_PATH_IMAGE004
。
10. Use of a process for the continuous hydrogenation of 2-nitropyridine derivative (II) according to claim 9 in the synthesis of a medicament for the treatment of cancer.
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