A method for reducing nitro compounds
By using ferrous halide and reducing agent to perform the reduction reaction of nitro compounds under mild conditions, the problems of high equipment requirements and poor ester tolerance in the prior art are solved, and a highly selective and environmentally friendly preparation of amino compounds is achieved. Suitable for industrial applications.
Patent Information
- Application Number
- CN202111465928.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2021-12-03
- Publication Date
- 2025-01-10
- Estimated Expiration
- 2041-12-03
AI Technical Summary
The existing nitro reduction methods have high equipment requirements, poor tolerance to ester groups, a lot of waste residue, and difficulty in operation and control, making it difficult to achieve high selective reduction reaction under mild conditions.
Ferrous halide and reducing agents (such as sodium borohydride) are used to carry out the reduction reaction under mild conditions, and amino compounds are obtained through post-treatment, which avoids harsh conditions of hydrogen and high pressure, and has good tolerance to functional groups such as ester groups.
It realizes high selective reduction of nitro compounds, has mild reaction conditions, simple operation and high yield, is suitable for industrial applications, and reduces heavy metal residue and waste residue generation.
Smart Images
Figure BDA0003391461180000011 
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Figure BDA0003391461180000041
Abstract
Description
Technical Field
[0001] The invention relates to a reduction method of a nitro compound and belongs to the technical field of chemical industry. Background Art
[0002] The reaction of reducing a nitro group to an amino group to obtain an amino compound is a reaction often involved in the preparation of various drugs or intermediate compounds. In the prior art, the reduction method of the nitro group includes reduction using Raney nickel / hydrogen, palladium carbon / hydrogen, hydrazine hydrate, stannous chloride, reducing metal / Lewis acid, sodium sulfide or hydrosulfite, etc. These methods obtain amino compounds with high or low yields. At the same time, these methods also have many defects, such as high requirements for equipment, poor tolerance to some special functional groups such as ester groups, or more waste residues, which are not conducive to environmental protection or operation control. Therefore, it is still necessary and very important to study a reduction method suitable for industrial application with mild reaction conditions, simple and easy operation and control, and no harsh requirements. Summary of the invention
[0003] The present invention aims to provide a method for reducing nitro groups to amino groups under mild conditions and with high selectivity. The method does not require harsh control conditions such as hydrogen and high pressure, has good tolerance to functional groups such as ester groups, has no heavy metal residues, and is easy to implement and apply.
[0004] Therefore, the present invention provides a preparation method, which comprises: adding ferrous halide and a reducing agent, subjecting compound 1 to a reduction reaction, and after the reaction is completed, subjecting the compound 1 to a post-treatment to obtain compound 2.
[0005]
[0006] in,
[0007] Y is methine (CH), carbon (C) or nitrogen (N);
[0008] The hydrogen on the ring where Y is located is optionally replaced by R, and R can be any number of fluorine, chlorine, bromine, iodine, C1-C6 (1 carbon to 6 carbon) alkyl, C1-C6 alkoxy, C3-C6 (3 carbon to 6 carbon) cycloalkyl, methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, isopropyl propionate, methyl butyrate, ethyl butyrate, C6-C10 (6 carbon to 10 carbon) aryl, C6-C10 heteroaryl, saturated or unsaturated three-membered to six-membered heterocyclic group, or a cyclic group such as C3-C6 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, saturated or unsaturated three-membered to six-membered heterocyclic group formed together with the carbon on the ring where Y is located.
[0009] The R may be connected to the ring at any position. The R may be 0, 1, 2, 3, 4, 5 or 6 groups that are the same or different at any position. When the R is a cyclic group such as an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclic group, it may be the aforementioned cyclic group formed together with the carbon on the ring where Y is located.
[0010] The cyclic group may optionally be substituted with halogen, such as fluorine, chlorine, bromine or iodine, or with an ester group, such as methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate or isopropyl acetate. In some embodiments, the cycloalkyl, aryl, heteroaryl or heterocyclic group may optionally be substituted with fluorine, chlorine, bromine, methyl formate, ethyl formate, isopropyl formate, methyl acetate or ethyl acetate.
[0011] In some embodiments, R is fluorine, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate, phenyl, benzyl, C6-C10 heteroaryl, saturated or unsaturated three-membered to six-membered heterocyclic group, or is a C6-C10 aryl, C6-C10 heteroaryl or saturated or unsaturated three-membered to six-membered heterocyclic group formed together with the two carbon atoms on the ring where Y is located. In some embodiments, R is chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, methyl formate, ethyl formate, methyl acetate, ethyl acetate, phenyl, benzyl, a saturated or unsaturated three-membered to six-membered heterocyclic group, or a saturated or unsaturated three-membered to six-membered heterocyclic group formed together with two adjacent carbon atoms on the ring where Y is located.
[0012] The heteroatom in the heterocyclic group or heteroaryl group can be at least one of oxygen, nitrogen or sulfur. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur and nitrogen.
[0013] The nitro group in compound 1 can be at any position connected to the ring. Compound 1 is subjected to a reduction reaction to obtain compound 2 in which the position corresponding to the nitro group is an amino group.
[0014] Therefore, the present invention also provides a preparation method, which comprises: adding ferrous halide and a reducing agent, subjecting compound i to a reduction reaction, and after the reaction is completed, subjecting compound j to a post-treatment to obtain compound j
[0015]
[0016] In the above-mentioned preparation method, the ferrous halide is at least one of ferrous chloride, ferrous bromide and ferrous iodide.
[0017] In the aforementioned preparation method, the reducing agent is at least one of sodium borohydride, potassium borohydride and lithium borohydride.
[0018] During the research, the inventors found that some compounds containing ester groups and / or halogen groups have poor tolerance to hydrazine hydrate, and it is difficult to obtain the target product with high quality and high yield using the known hydrazine hydrate reduction method. However, the method using the combination of ferrous halide and the reducing agent of the present invention has good tolerance to compounds containing ester groups and / or halogen groups, and the target amino compound can be obtained simply and in high yield. Compared with the method using a combination of hydrogen and a metal catalyst, or a combination of ferrous sulfate and hydrazine hydrate, or a combination of ferrous chloride and hydrazine hydrate, the conditions are more mild and controllable, and the reaction conversion rate and yield are relatively higher, which is more conducive to application implementation.
[0019] According to an embodiment of the present invention, in the aforementioned preparation method, the reaction solvent of the reduction reaction may be at least one of tetrahydrofuran, acetonitrile, toluene, ethyl acetate, dichloromethane, methanol, ethanol, isopropanol and isopropyl acetate. In some embodiments, the reaction solvent is preferably tetrahydrofuran and / or acetonitrile, which is conducive to the reaction and the acquisition of the target product.
[0020] For each gram of compound 1 or compound i, the amount of the reaction solvent used can be 5 ml-30 ml, or 8 ml-20 ml, or 10 ml, or 15 ml.
[0021] In the aforementioned preparation method, the reaction temperature of the reduction reaction may be 10°C-40°C. In some embodiments, the reaction temperature of the reduction reaction is 20°C-30°C. In some embodiments, the reaction temperature of the reduction reaction is 25°C-30°C. In some embodiments, the reaction temperature of the reduction reaction is 10°C-25°C.
[0022] The reaction time of the reduction reaction can be 5-36 hours.
[0023] According to an embodiment of the present invention, the molar ratio of compound 1 or compound i to the ferrous halide can be 1:0.8-1:2.5.
[0024] The molar ratio of compound 1 or compound i to the reducing agent can be 1:1-1:4.
[0025] In the aforementioned preparation method, the post-treatment includes: adding water to the reaction system, quenching the reaction, and then extracting with an ester solvent, and the obtained organic phase is distilled under reduced pressure to remove the solvent to obtain a crude compound 2 or compound j. The crude product can be further processed to obtain a higher quality product. In some embodiments, the crude product is washed, pulped, crystallized, or subjected to silica gel column chromatography using petroleum ether and ester solvents as eluents to obtain a compound 2 or compound j product.
[0026] The volume ratio of petroleum ether to ester solvent can be 5: 1-50: 1. In some embodiments, the volume ratio of petroleum ether to ester solvent is 10: 1-40: 1, or 15: 1, or 20: 1, or 25: 1, or 30: 1, or 35: 1.
[0027] The ester solvent may be at least one of ethyl acetate and isopropyl acetate. For each gram of compound 1 or compound i, the amount of the ester solvent used during extraction may be 5 ml-50 ml, or 10 ml-30 ml.
[0028] According to an embodiment of the present invention, in some embodiments, the preparation method comprises: compound 1 or compound i is subjected to a reduction reaction in tetrahydrofuran at 10°C-40°C under the condition of adding ferrous chloride and sodium borohydride, and after the reaction is completed, post-processing is performed to prepare compound 2 or compound j.
[0029] The preparation method provided by the present invention can simply obtain a compound in which a nitro group is reduced to an amino group, has mild reaction conditions, is easy to operate and control, has a high yield, and is easy to implement.
[0030] In the description of this specification, the description of the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples, unless they are contradictory.
[0031] In the present invention, h means hour, g means gram, mL means milliliter, and TLC means thin layer chromatography. In the present invention, TLC is used to confirm whether the reaction is complete, and the reaction is considered complete when the reaction raw materials disappear or are not displayed in the TLC detection.
[0032] In the present invention, when referring to numerical values, regardless of whether "about" or "approximately" is used, based on the disclosed numerical values, the error of the numerical values does not exceed ±10%, that is, the error may be -10% to 10%, ±10%, ±8%, ±5%, ±2%, ±1%, or ±0.5%, etc. DETAILED DESCRIPTION
[0033] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.
[0034] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.
[0035] Example 1-Example 3 and Comparative Example 1 Reaction Formula
[0036]
[0037] Example 1
[0038] Add 2g of compound a, 1.2g of ferrous chloride and 20ml of tetrahydrofuran to a single-mouth bottle, and add 643mg of sodium borohydride under nitrogen protection after the addition; then react at 28°C for 12 hours, TLC detection confirms that the reaction is complete, and stop the reaction; add 40ml of water to the reaction system to quench the reaction, and then extract with ethyl acetate (20ml*3 times), and distill the obtained organic phase under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 20:1 to obtain b: 1.62g of yellow solid product, with a yield of 93%; detection:
[0039] 1 H NMR (400MHz, DMSO-d6) δ7.51 (s, 1H), 7.38 (d, J = 9.4Hz, 1H), 6.82 (d, J = 6.9Hz, 2H), 5.22 (s, 2H), 4.32 (dd, J = 14.1, 7.0Hz, 2H), 1.32 (t, J = 7.1Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ158.82,148.66,145.09,144.77,127.34,117.25,113.65,111.98,104.41,60.86,14.12.
[0040] Example 2
[0041] 2 g of compound a, 1.2 g of ferrous chloride and 20 ml of tetrahydrofuran as solvent were added to a single-mouth bottle. After the addition, 917 mg of potassium borohydride was added under nitrogen protection and stirring, and then the reaction was carried out at 28°C for 10 hours. TLC detection confirmed that the reaction was complete and the reaction was stopped; 40 ml of water was added to the reaction system to quench the reaction, and then extracted with ethyl acetate (20 ml*3 times), and the obtained organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 20:1 to obtain b: 1.47 g of yellow solid product with a yield of 84%.
[0042] Example 3
[0043] 2g of compound a, 1.2g of ferrous chloride and 20ml of acetonitrile were added to a single-mouth bottle. After the addition, 643mg of sodium borohydride was added under nitrogen protection while stirring, and then the reaction was carried out at 28°C for 12 hours. TLC detection confirmed that the reaction was complete and the reaction was stopped; 40ml of water was added to the reaction system to quench the reaction, and then extracted with ethyl acetate (20ml*3 times), and the obtained organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 20:1 to obtain b: 1.51g of yellow solid product with a yield of 87%.
[0044] Comparative Example 1:
[0045] 2g of compound a, 1.4g of ferrous sulfate and 20ml of acetonitrile were added to a single-mouth bottle. After the addition, 643mg of sodium borohydride was added under nitrogen protection while stirring, and then the reaction was carried out at 28°C for 12 hours. TLC detection confirmed that the reaction was complete and the reaction was stopped; 40ml of water was added to the reaction system to quench the reaction, and then extracted with ethyl acetate (20ml*3 times), and the obtained organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 20:1 to obtain b: 1.02g of yellow solid product, with a yield of 59%.
[0046] Example 4
[0047]
[0048] 2g of compound c, 1.4g of ferrous chloride and 20ml of tetrahydrofuran were added to a single-mouth bottle. After the addition, nitrogen was protected. 897mg of sodium borohydride was added under stirring, and then the reaction was carried out at 28°C for 15 hours. TLC detection confirmed that the reaction was complete and the reaction was stopped; 40ml of water was added to the reaction system to quench the reaction, and then extracted with ethyl acetate (20ml*3 times). The obtained organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 40:1 to obtain d: 1.46g of yellow oily product, with a yield of 86%; detection:
[0049] 1 H NMR (400MHz, DMSO-d6) δ6.92(d,J=8.3Hz,2H),6.54(d,J=8.3Hz,2H),4.98(s,2H),4.16–3.94(m,2H),3.44(s,2H),1.18(t,J=7.1Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ171.76,147.38,129.61,121.19,113.88,59.95,39.71,14.05.
[0050] Reaction formula of Example 5 and Comparative Example 2:
[0051]
[0052] Example 5
[0053] 2g of compound e, 1.4g of ferrous chloride and 20ml of tetrahydrofuran were added to a single-mouth bottle. After the addition, 1.04g of sodium borohydride was added under nitrogen protection while stirring, and then the reaction was carried out at 28°C for 12 hours. TLC detection confirmed that the reaction was complete and the reaction was stopped; 40ml of water was added to the reaction system to quench the reaction, and then extracted with ethyl acetate (20ml*3 times), and the obtained organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 40:1 to obtain f: 1.61g of yellow oily product with a yield of 97%; detection:
[0054] 1 H NMR (400MHz, DMSO-d6) δ7.24 (s, 1H), 7.18–7.07 (m, 2H), 6.83 (dt, J = 7.0, 2.2Hz, 1H), 5.37 (s, 2H), 3.80 (s, 3H); 13 C NMR (101MHz, DMSO-d6) δ166.82,148.98,130.25,129.06,118.38,116.44,114.17,51.76.
[0055] Comparative Example 2:
[0056] 2 g of compound e, 1.7 g of ferrous sulfate and 20 ml of tetrahydrofuran were added to a single-mouth bottle. After the addition was completed, 1.04 g of sodium borohydride was added under nitrogen protection while stirring, and then the reaction was carried out at 28°C for 12 hours. TLC detection confirmed that the reaction was complete and the reaction was stopped; 40 ml of water was added to the reaction system to quench the reaction, and then extracted with ethyl acetate (20 ml*3 times), and the obtained organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 40:1 to obtain f: 1.33 g of yellow oily product with a yield of 80%.
[0057] Example 6
[0058]
[0059] Add 2g of compound g, 1.4g of ferrous chloride and 20ml of tetrahydrofuran to a single-mouth bottle, and after the addition, add 0.87g of sodium borohydride under nitrogen protection, and then react at 26°C for 12 hours. TLC detection confirms that the reaction is complete and stops the reaction; add 40ml of water to the reaction system to quench the reaction, and then extract with ethyl acetate (20ml*3 times), and distill the obtained organic phase under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 10:1 to obtain h: 1.61g of yellow oily product, with a yield of 94%; detection:
[0060] 1 H NMR (400MHz, DMSO-d6) δ7.80(d,J=8.3Hz,1H),7.14(d,J=8.3Hz,1H),6.45(s,2H),3.79(s,3H); 13 C NMR (101MHz, DMSO-d6) δ164.10,144.91,133.91,132.97,126.09,120.35,51.77.
[0061] Example 7
[0062]
[0063] 2g of compound i, 1.1g of ferrous chloride and 20ml of tetrahydrofuran were added to a single-mouth bottle. After the addition, 700mg of sodium borohydride was added under nitrogen protection while stirring, and then the reaction was carried out at 26°C for 12 hours. TLC detection confirmed that the reaction was complete and the reaction was stopped; 40ml of water was added to the reaction system to quench the reaction, and then extracted with ethyl acetate (20ml*3 times), and the obtained organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 5:1 to obtain j: 1.69g of yellow oily product, with a yield of 96%; detection:
[0064] 1 H NMR (400MHz, DMSO-d6) δ5.83(s,2H),2.99(t,J=7.1Hz,2H),1.72–1.54(m,2H),0.95(t,J=7.4Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ154.06,143.67,133.33,32.47,21.96,13.09.
[0065] Example 8
[0066]
[0067] Add 2g of compound K, 0.975g of ferrous chloride and 20ml of acetonitrile to a single-mouth bottle, and after the addition, add 726mg of sodium borohydride under nitrogen protection, and then react at 26°C for 14 hours. TLC detection confirms that the reaction is complete and stops the reaction; add 40ml of water to the reaction system to quench the reaction, and then extract with ethyl acetate (20ml*3 times), and distill the obtained organic phase under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography with an eluent of petroleum ether / ethyl acetate = 5:1 to obtain 1.67g of a yellow oily product with a yield of 95%; detection:
[0068] 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=8.7Hz,1H),7.05(d,J=2.1Hz,1H),6.77(dd,J=8.7,2.2Hz,1H),5.54(s,2H); 13 C NMR (101MHz, DMSO-d6) δ147.70,143.16,138.45,131.07,122.46,114.91,103.41.
[0069] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
Claims
1. A preparation method comprising: Under the condition of adding ferrous halide and reducing agent, compound 1 undergoes reduction reaction, and after the reaction is completed, compound 2 is prepared by post-treatment. in, The compound 1 is The ferrous halide is ferrous chloride; the reducing agent is sodium borohydride; the reaction solvent of the reduction reaction is tetrahydrofuran; the reaction temperature of the reduction reaction is 10°C-40°C; or, The compound 1 is The ferrous halide is ferrous chloride; the reducing agent is sodium borohydride; the reaction solvent of the reduction reaction is acetonitrile; the reaction temperature of the reduction reaction is 10°C-40°C; The molar ratio of the compound 1 to the ferrous halide is 1:0.8-1:2.5; the molar ratio of the compound 1 to the reducing agent is 1:1-1:
4.
2. The preparation method according to claim 1, wherein The reaction time of the reduction reaction is 5 hours to 36 hours.
3. A method for preparing compound J, comprising: Under the condition of adding ferrous halide and reducing agent, compound i is subjected to reduction reaction in tetrahydrofuran at 10°C-40°C. After the reaction is completed, compound j is prepared by post-treatment. Wherein, the ferrous halide is ferrous chloride; the reducing agent is sodium borohydride; Among them, the feeding molar ratio of compound i to the ferrous halide is 1:0.8-1:2.5, and the feeding molar ratio of compound i to the reducing agent is 1:1-1:
4.
4. The preparation method according to any one of claims 1 to 2, wherein: The post-treatment includes: adding water to the reaction system to quench the reaction, then extracting with an ester solvent, and distilling the organic phase under reduced pressure to remove the solvent to obtain a crude compound 2.
5. The preparation method according to claim 4, wherein The crude product is washed, slurried, crystallized or subjected to silica gel column chromatography using petroleum ether and ethyl acetate as eluent to obtain compound 2 product; the volume ratio of petroleum ether to ethyl acetate is 5:1-50:1.