CN115677587A - Method for preparing 6-chloro-5-nitro-1-hydro-indazole - Google Patents
Method for preparing 6-chloro-5-nitro-1-hydro-indazole Download PDFInfo
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- 238000006396 nitration reaction Methods 0.000 claims abstract description 13
- SXVCMKGCWGVSSX-UHFFFAOYSA-N 6-chloro-5-nitro-1h-indazole Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1NN=C2 SXVCMKGCWGVSSX-UHFFFAOYSA-N 0.000 claims abstract description 10
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Abstract
The invention provides a method for preparing 6-chloro-5-nitro-1H-indazole, and belongs to the field of medicine synthesis. The method comprises the following steps: (1) Carrying out nitration reaction on the compound A and nitric acid to obtain a compound B; x is halogen; (2) And reacting the compound B with hydrazine hydrate to obtain a compound c, namely 6-chloro-5-nitro-1H-indazole. The starting raw materials adopted in the method are easy to obtain and have low price; the method provided by the invention is simple and safe to operate, does not relate to a high-risk process, and the obtained product 6-chloro-5-nitro-1-hydro-indazole is high in purity and yield and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing 6-chloro-5-nitro-1-hydro-indazole.
Background
Coronaviruses (coronavirus) belong to the genus coronaviruses of the family coronaviridae in a systematic classification, and mature coronaviruses are coronal or coronal under an electron microscope, and are named coronaviruses, which are likely to cause central nervous system diseases, common cold, lower respiratory tract infection and diarrhea. Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a highly pathogenic, large-scale epidemic of zoonosis. The novel coronavirus pneumonia caused by SARS-CoV-2 (COVID-19) in the global pandemic, variants such as the Deltay and Oromkronn variants (Omicron) continue to emerge, leading to diminished or even ineffective protection of the new corona vaccine.
Symptoms of SARS-CoV-2 virus infection range from asymptomatic disease to moderate and severe pneumonia, as well as life-threatening complications including hypoxic respiratory failure, acute respiratory distress syndrome, multiple system organ failure, and ultimately death. At present, the prevention and cure of virus mainly depend on vaccine and medicine. The vaccine itself has certain limitations: the immunization rate is low, and effective group immunity is difficult to generate; the immunity hardly generates effective immunity for high risk people, such as the elderly and people with immunodeficiency; due to the lack of post-translational correction mechanisms of viral RNA polymerase, development of new vaccines is continually ongoing in the face of continuous viral mutations, and it is difficult to generate sufficient amounts of new vaccines in a short time at the early stage of rapid epidemic. Therefore, antiviral drug research remains a hot topic in the field of antiviral research.
The non-covalent Mpro small molecule inhibitor S-217662 (CAS: 2647530-73-0) reported by Nippon salt Yeyi pharmaceutical Co, which currently has reported some positive clinical findings, is currently in clinical stage 2/3. The compound can obviously inhibit various SARS-CoV-2 variant strains including alpha, beta, gamma, omicron and the like, and shows that the compound has wide application potential as a therapeutic agent for treating new crowns. And S-217622 showed broad antiviral activity against a range of coronaviruses. The large-scale synthesis of S-217662 with high yield, high purity and low cost is of great significance.
6-chloro-5-nitro-1 hydro-indazole is a key intermediate for the synthesis of S-217662. Chinese patent application No. 202210418619.9 discloses a method for synthesizing 6-chloro-5-nitro-1-hydro-indazole, the route of which is shown below. The method takes a compound 1 as a starting material, the compound 1 is suspended in water (80 mL) and concentrated hydrochloric acid (25mL, 0.3 mol), naNO is added at 0 DEG C 2 Aqueous solution (6.9 g, 0.1mol) was added dropwise to the above solution, followed by stirring for 20min, filtration, pre-cooled NaBF 4 An aqueous solution (40 mL) (12.G, 0.1 mol) was added to the above filtrate, and the mixture was stirred for 40min. Stirring was stopped, filtration was carried out, the filter cake was washed with cold ethanol and diethyl ether, the filter cake was collected and dried to obtain a diazonium salt (11.5g, 0.05mol). Dissolving the diazonium salt in CHCl 3 (100 mL), KOAc (8.15g, 0.78mol) was added to the solution, and the mixture was stirred at room temperature for 2 hours to complete the reaction, and the stirring was stopped. The reaction was quenched with water (50 mL), extracted with DCM (50 mL. Times.3), the organic phases combined, washed with brine, anhydrous Na 2 SO 4 Drying, filtering, concentrating, and recrystallizing to obtain compound 2, namely 6-chloro-5-nitro-1-hydro-indazole.
However, the above method has the following problems: (1) The starting raw material (namely the compound 1) adopted by the method is expensive and reaches 5500 yuan/kg, so that the production cost is increased; (2) The diazotization reaction related to the method belongs to a high-risk process and is not suitable for industrial production; (3) NaNO used in the above method 2 Easily produce genotoxic impurities which are difficult to remove; (4) Furthermore, the inventors of the present invention repeated the above process and found that the yield was only 35%, far from the claimed 80%.
In order to overcome the above problems, it is highly desirable to develop a method for preparing 6-chloro-5-nitro-1-hydro-indazole with low cost, high yield and high purity, which is suitable for industrial production.
Disclosure of Invention
The invention aims to provide a method for preparing 6-chloro-5-nitro-1-hydro-indazole, which has low cost, high yield and high purity and is suitable for industrial production.
The present invention provides a process for preparing 6-chloro-5-nitro-1 h-indazole comprising the steps of:
(1) Carrying out nitration reaction on the compound A and nitric acid to obtain a compound B; x is halogen;
(2) And reacting the compound B with hydrazine hydrate to obtain a compound c, namely 6-chloro-5-nitro-1H-indazole.
Further, X is chlorine or fluorine, preferably fluorine.
Further, in the step (1), the nitration reaction is carried out under the action of a catalyst, and the catalyst is concentrated sulfuric acid; the equivalent ratio of compound a, nitric acid and catalyst is 1: (3-4): (2-3); the nitric acid is concentrated nitric acid;
the solvent of the nitration reaction is concentrated sulfuric acid, and the mass of the compound A and the solvent is 1: (5-30);
the temperature of the nitration reaction is-30 to 30 ℃ and the time is 1 to 60min.
Further, the equivalent ratio of compound a, nitric acid and catalyst is 1:3.5:2.8 of;
the mass ratio of the compound A to the solvent is 1: (12-20);
the temperature of the nitration reaction is-20 to 25 ℃, and the time is 30min.
Further, in the step (1), after the nitration reaction is finished, the following post-treatment steps are included: and pouring the reaction solution into ice water, stirring, adding dichloromethane for extraction, washing an organic phase with a saturated sodium bicarbonate solution, and drying to obtain a compound B.
Further, in the step (2), the mass ratio of the compound B to the hydrazine hydrate is (0.20 to 1.50): 1;
the solvent of the reaction is an organic solvent;
the reaction temperature is 50-70 ℃ and the reaction time is 2-7 h.
Further, in the step (2), the mass ratio of the compound B to the hydrazine hydrate is (0.44-1.03): 1;
the organic solvent is dimethyl sulfoxide or N, N-dimethylformamide;
the reaction temperature is 60 ℃ and the reaction time is 4h.
Further, in the step (2), the hydrazine hydrate is 40% hydrazine hydrate.
Further, in step (2), the reaction is in I 2 In the presence of said compounds B and I 2 The mass ratio of (4-6): 0.01, preferably 2.2:0.01.
further, in the step (2), after the reaction is finished, the method further comprises the following post-treatment steps: water was added to the reaction solution, and the mixture was filtered, and the solid was collected and dried to obtain compound c.
In the invention, the concentrated sulfuric acid refers to a sulfuric acid aqueous solution with the mass fraction of more than or equal to 70 percent, and the density of the commercially available concentrated sulfuric acid adopted in the embodiment is 1.84g/mL; "concentrated nitric acid" means fuming nitric acid having a concentration of 8mol/L or more, and the mass fraction of commercially available concentrated nitric acid used in the examples was 98%.
Compared with the prior art, the method for preparing the 6-chloro-5-nitro-1-hydro-indazole has the following beneficial effects:
(1) The initial raw materials adopted in the method are easy to obtain, can be obtained from commercial products, and have low price;
(2) The method is simple and safe to operate, does not relate to high-risk processes, and is suitable for industrial production;
(3) The raw materials adopted by the method are safe and nontoxic, and NaNO is not used 2 The genotoxic impurities which are difficult to remove are not generated;
(4) The product 6-chloro-5-nitro-1H-indazole prepared by the method has high purity, high yield and wide application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1: preparation of 6-chloro-5-nitro-1-hydro-indazole obtained in example 1 1 H NMR spectrum.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Example 1: process for preparing 6-chloro-5-nitro-1-hydro-indazoles
The method comprises the following steps: the compound a (7.5g, 1eq) was dissolved in concentrated sulfuric acid (50mL, 92g), stirred, and cooled to-20 ℃. Keeping at-20 ℃, dropwise adding mixed acid of concentrated sulfuric acid (11.77g, 2.8eq) and concentrated nitric acid (9.45g, 3.5eq), keeping at-20 ℃ after dropwise adding, stirring for reaction for 30min, then returning to room temperature under a stirring state, pouring the reaction liquid into ice water, stirring, adding DCM (dichloromethane, 3X 2 mL), extracting, taking an organic phase, washing with saturated sodium bicarbonate solution, drying with anhydrous magnesium sulfate, filtering to remove the magnesium sulfate, and carrying out rotary evaporation on the filtrate to remove the solvent, thereby obtaining an intermediate compound b (2, 4-dichloro-5-nitro-benzaldehyde). The yield is 95 percent, and the purity is 89.9 percent.
Step two: a50 mL three-necked flask was charged with 2.2g of the compound b prepared in step one, iodine (I) 2 ) 0.01g, 10mL of DMSO (dimethyl sulfoxide) was dissolved with stirring. Then 5g of 40% hydrazine hydrate is added and stirred evenly. The reaction was monitored by thin layer chromatography with heating and temperature control at 60 ℃ and was complete after 4 hours. To the reaction mixture was added 100mL of water, and the mixture was filtered to collect a yellow solid and dried to obtain compound c (i.e., 6-chloro-5-nitro-1-hydro-indazole). The yield is 56 percent, and the purity is 98.6 percent. 1 H(NMR,d 6 -DMSO)＝8.68(s,1H),8.37(s,1H),7.93(s,1H)。
As can be seen, the total yield of the product of 6-chloro-5-nitro-1 h-indazole prepared using the method of example 1 was 53.2% with a purity of 98.6%.
Example 2: process for preparing 6-chloro-5-nitro-1-hydro-indazoles
The method comprises the following steps: the compound a (7.5g, 1eq) was dissolved in concentrated sulfuric acid (50mL, 92g), stirred, and cooled to 0 ℃. Keeping at 0 ℃, dropwise adding mixed acid of concentrated sulfuric acid (11.77g, 2.8eq) and concentrated nitric acid (9.45g, 3.5eq), keeping at 0 ℃ after dropwise adding, stirring for reaction for 30min, then returning to room temperature under stirring filling, pouring the reaction liquid into ice water, stirring, adding DCM (dichloromethane, 3X 2 mL) for extraction, taking the organic phase, washing with saturated sodium bicarbonate solution, drying with anhydrous magnesium sulfate, filtering to remove magnesium sulfate, and performing rotary evaporation on the filtrate to remove the solvent to obtain an intermediate compound b (2, 4-dichloro-5-nitro-benzaldehyde). The yield is 96 percent, and the purity is 78 percent.
Step two: a50 mL three-necked flask was charged with 2.2g of the compound b prepared in step one, iodine (I) 2 ) 0.01g, 10mL of DMSO (dimethyl sulfoxide) was dissolved with stirring. Then 5g of 40% hydrazine hydrate is added and stirred evenly. The reaction was monitored by thin layer chromatography with heating and temperature control at 60 ℃ and was complete after 4 hours. To the reaction mixture was added 100mL of water, and the mixture was filtered to collect a yellow solid and dried to obtain compound c (i.e., 6-chloro-5-nitro-1-hydro-indazole). The yield was 42% and the purity was 94.1%. 1 H(NMR,d 6 -DMSO)＝8.68(s,1H),8.37(s,1H),7.93(s,1H)。
As can be seen, the total yield of the product from the preparation of 6-chloro-5-nitro-1 h-indazole using the method of example 2 was 40.32% with a purity of 94.1%.
Example 3: process for preparing 6-chloro-5-nitro-1-hydro-indazoles
The method comprises the following steps: compound a (17g, 1eq) was dissolved in concentrated sulfuric acid (187mL, 344.08g), stirred, and temperature controlled at 25 ℃. Keeping at 25 ℃, dropwise adding mixed acid of concentrated sulfuric acid (29.8g, 2.8eq) and concentrated nitric acid (24.2g, 3.5eq), keeping at 25 ℃ after dropwise adding, stirring for reaction for 30min, then returning to room temperature under stirring filling, pouring the reaction liquid into ice water, stirring, adding DCM (dichloromethane, 3 × 25mL) for extraction, taking the organic phase, washing with saturated sodium bicarbonate solution, drying with anhydrous magnesium sulfate, filtering to remove magnesium sulfate, and performing rotary evaporation on the filtrate to remove the solvent to obtain an intermediate compound b (2, 4-dichloro-5-nitro-benzaldehyde). The yield is 99 percent, and the purity is 99 percent.
Step two: to a 50mL three-necked flask was added 2.2g of the compound b prepared in step one, iodine (I) 2 ) 0.01g, 10mL of DMSO (dimethylsulfoxide) was dissolved with stirring. Then 5g of 40% hydrazine hydrate is added and stirred evenly. The reaction was monitored by thin layer chromatography with heating and temperature control at 60 ℃ and was complete after 4 hours. To the reaction mixture was added 100mL of water, and the mixture was filtered to collect a yellow solid and dried to obtain compound c (i.e., 6-chloro-5-nitro-1-hydro-indazole). The yield is 85 percent, and the purity is 98.1 percent. 1 H(NMR,d 6 -DMSO)＝8.68(s,1H),8.37(s,1H),7.93(s,1H)。
As can be seen, the total yield of the product from the preparation of 6-chloro-5-nitro-1 h-indazole using the method of example 3 was 84.15% with a purity of 98.1%.
Example 4: process for preparing 6-chloro-5-nitro-1-hydro-indazoles
The method comprises the following steps: compound a (17g, 1eq) was dissolved in concentrated sulfuric acid (187mL, 344.08g), stirred, and temperature controlled at 25 ℃. Keeping at 25 ℃, dropwise adding mixed acid of concentrated sulfuric acid (29.8g, 2.8eq) and concentrated nitric acid (24.2g, 3.5eq), keeping at 25 ℃ after dropwise adding, stirring for reaction for 30min, then returning to room temperature under stirring filling, pouring the reaction liquid into ice water, stirring, adding DCM (dichloromethane, 3 × 25mL) for extraction, taking the organic phase, washing with saturated sodium bicarbonate solution, drying with anhydrous magnesium sulfate, filtering to remove magnesium sulfate, and performing rotary evaporation on the filtrate to remove the solvent to obtain an intermediate compound b (2, 4-dichloro-5-nitro-benzaldehyde). The yield is more than 99 percent, and the purity is 99 percent.
Step two: a50 mL three-necked flask was charged with 9mL of DMF (N, N-dimethylformamide) and 40% hydrazine hydrate (1.95g, 3.2eq), and then cooled to 0 ℃ to add the compound b prepared in the first step (2.0 g,1.0 eq) with stirring. After the addition, slowly heating to room temperature, continuously stirring for 2h, then heating to 60 ℃, and continuing to react for 1h. The reaction progress was monitored by thin layer chromatography and after 4 hours the reaction was complete. To the reaction mixture was added 100mL of water, and the mixture was filtered to collect a yellow solid and dried to obtain compound c (i.e., 6-chloro-5-nitro-1-hydro-indazole). The yield is 90%, and the purity is 95.9%. 1 H(NMR,d 6 -DMSO)＝8.68(s,1H),8.37(s,1H),7.93(s,1H)。
As can be seen, the total yield of the product from the preparation of 6-chloro-5-nitro-1 h-indazole using the method of example 4 was 89.1% with a purity of 95.9%.
In summary, the present invention provides a method for preparing 6-chloro-5-nitro-1-hydro-indazole. The starting raw materials adopted in the method are easy to obtain and have low price; the method provided by the invention is simple and safe to operate, does not relate to a high-risk process, and the obtained product 6-chloro-5-nitro-1-hydro-indazole is high in purity and yield and suitable for industrial production.
Claims (10)
1. A method of making a 6-chloro-5-nitro-1-hydro-indazole, characterized by: the method comprises the following steps:
(1) Carrying out nitration reaction on the compound A and nitric acid to obtain a compound B; x is halogen;
(2) And reacting the compound B with hydrazine hydrate to obtain a compound c, namely 6-chloro-5-nitro-1H-indazole.
2. The method of claim 1, wherein: x is chlorine or fluorine, preferably fluorine.
3. The method according to claim 1 or 2, characterized in that: in the step (1), the nitration reaction is carried out under the action of a catalyst, and the catalyst is concentrated sulfuric acid; the equivalent ratio of compound a, nitric acid and catalyst is 1: (3-4): (2-3); the nitric acid is concentrated nitric acid;
the solvent of the nitration reaction is concentrated sulfuric acid, and the mass of the compound A and the solvent is 1: (5-30);
the temperature of the nitration reaction is-30 to 30 ℃ and the time is 1 to 60min.
4. The method of claim 3, wherein: the equivalent ratio of compound a, nitric acid and catalyst is 1:3.5:2.8;
the mass ratio of the compound A to the solvent is 1: (12-20);
the temperature of the nitration reaction is-20 to 25 ℃, and the time is 30min.
5. The method according to claim 1 or 2, characterized in that: in the step (1), after the nitration reaction is finished, the method further comprises the following post-treatment steps: and pouring the reaction solution into ice water, stirring, adding dichloromethane for extraction, washing an organic phase with a saturated sodium bicarbonate solution, and drying to obtain a compound B.
6. The method according to claim 1 or 2, characterized in that: in the step (2), the mass ratio of the compound B to the hydrazine hydrate is (0.20-1.50): 1;
the solvent for the reaction is an organic solvent;
the reaction temperature is 50-70 ℃ and the reaction time is 2-7 h.
7. The method of claim 6, wherein: in the step (2), the mass ratio of the compound B to the hydrazine hydrate is (0.44-1.03): 1;
the organic solvent is dimethyl sulfoxide or N, N-dimethylformamide;
the reaction temperature is 60 ℃ and the reaction time is 4h.
8. The method of claim 7, wherein: in the step (2), the hydrazine hydrate is 40% hydrazine hydrate.
9. The method according to claim 1 or 2, characterized in that: in step (2), the reaction is in I 2 In the presence of said compounds B and I 2 The mass ratio of (4-6): 0.01, preferably 2.2:0.01.
10. the method according to any one of claims 1-9, wherein: in the step (2), after the reaction is finished, the method further comprises the following post-treatment steps: water was added to the reaction solution, and the mixture was filtered to collect a solid, which was then dried to obtain compound c.
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