CN115504937A - Method for synthesizing axitinib intermediate 6-aminoindazole by tubular reactor - Google Patents
Method for synthesizing axitinib intermediate 6-aminoindazole by tubular reactor Download PDFInfo
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- KEJFADGISRFLFO-UHFFFAOYSA-N 1H-indazol-6-amine Chemical compound NC1=CC=C2C=NNC2=C1 KEJFADGISRFLFO-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 18
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 title claims abstract description 17
- 229960003005 axitinib Drugs 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- 239000000463 material Substances 0.000 claims abstract description 44
- ORZRMRUXSPNQQL-UHFFFAOYSA-N 6-nitro-1h-indazole Chemical compound [O-][N+](=O)C1=CC=C2C=NNC2=C1 ORZRMRUXSPNQQL-UHFFFAOYSA-N 0.000 claims abstract description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- 238000001816 cooling Methods 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 12
- 229910000510 noble metal Inorganic materials 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 238000007605 air drying Methods 0.000 claims description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 3
- 239000000047 product Substances 0.000 abstract description 18
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000002474 experimental method Methods 0.000 description 7
- 239000007789 gas Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000003622 immobilized catalyst Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- -1 (3- (2- (pyridine-2-yl) vinyl) -1H-indazol-6-yl) thio Chemical group 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000385 effect on melanoma Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 229910052642 spodumene Inorganic materials 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J21/00—Catalysts comprising the elements, oxides, or hydroxides of magnesium, boron, aluminium, carbon, silicon, titanium, zirconium, or hafnium
- B01J21/18—Carbon
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/42—Platinum
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/44—Palladium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J8/00—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes
- B01J8/02—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with stationary particles, e.g. in fixed beds
- B01J8/06—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with stationary particles, e.g. in fixed beds in tube reactors; the solid particles being arranged in tubes
Abstract
The invention provides a method for synthesizing an axitinib intermediate 6-aminoindazole by using a tubular reactor, wherein the 6-aminoindazole is synthesized by the following steps: mixing 6-nitroindazole and an organic solvent to obtain a material I, and conveying the material I to a preheating module; the preheated material I enters a reaction module to react with hydrogen; the reaction product enters a cooling module and is cooled to 35 ℃; concentrating and cooling the reaction solution to 2 ℃, cooling and crystallizing for 3 hours, throwing materials, and drying wet products to obtain 6-aminoindazole; has the advantages that: the method has the advantages of less side reaction, reduction of hydrogen leakage, reduction of energy consumption, improvement of product yield and purity, reduction of catalyst cost, small occupied area of equipment, simplicity in operation, reduction of labor, reduction of production cost and guarantee of production economy.
Description
Technical Field
The invention relates to the field of compound synthesis methods, in particular to a method for synthesizing an axitinib intermediate 6-aminoindazole by using a tubular reactor.
Background
Axitinib, english name (axitinib), chinese alias (E) -N-methyl-2- ((3- (2- (pyridin-2-yl) vinyl) -1H-indazol-6-yl) thio) benzamide, english alias (E) -N-methyl-2- ((3- (2- (pyridine-2-yl) vinyl) -1H-indazol-6-yl) thio) benzamide CAS: 319460-85-0, molecular formula C22H18N4OS, developed by spodumene pharmaceutical company, usa, first marketed in usa in 2012. The product is effective when being orally taken, can target on Vascular Endothelial Growth Factor (VEGF) receptor tyrosine kinase, strongly and selectively inhibit the phosphorylation of VEGF-dependent receptors, thereby interrupting downstream signal transmission, finally leading tumor cells to be incapable of proliferation and even death, and having remarkable curative effect on melanoma, renal carcinoma, adenocarcinoma, thyroid cancer, breast cancer, lung cancer and colorectal cancer. Is suitable for treating late-stage renal cell carcinoma after the previous systemic treatment failure.
The method for synthesizing 6-aminoindazole in the existing synthesis method mainly comprises the following routes:
6-nitroindazole is dissolved in ethanol, a catalytic amount of raney nickel (5% -10%) is added, then refluxing is carried out, about 8eq of 80% hydrazine hydrate is added in portions, refluxing is carried out for about 0.5 hour, raney nickel is removed by filtration, ethanol is recovered under reduced pressure, and precipitated 1H-indazol-6-amine is obtained with the yield of 96%. The catalyst is easy to inactivate in the large-scale production process of the reaction, so that the cost is uncontrollable and the reaction ratio is not uniform and stable; the reaction process is easy to flush and has violent reaction and large potential safety hazard. In view of the above, it is not reasonable to synthesize 6-aminoindazole by Raney nickel hydrazine hydrate reduction, either from the viewpoint of safety or economic efficiency.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides a method for synthesizing an axitinib intermediate 6-aminoindazole by using a tubular reactor.
The new technical scheme of the invention is as follows: a method for synthesizing an axitinib intermediate 6-aminoindazole by using a tubular reactor, wherein the 6-aminoindazole is synthesized by the following steps:
1) Mixing a raw material 6-nitroindazole and an organic solvent to obtain a material I, conveying the material I to a preheating module of a tubular reactor through a flow pump, and preheating the material I in the preheating module; the concentration of the 6-nitroindazole in the organic solvent is 0.1-0.5mol/L;
2) The preheated material I enters a reaction module of a tubular reactor, the reaction module is immobilized with active carbon to load a noble metal catalyst, and the mass ratio of the 6-nitroindazole to the catalyst is 1 (0.01-0.10); hydrogen is conveyed to a reaction module of the tubular reactor through a flow pump, the hydrogen and a material I react in the reaction module, the reaction temperature is 80-140 ℃, the reaction pressure is 0.1-1.0 MPa, the residence time of the material I and the hydrogen in the reaction module is 20-50 s, and the molar ratio of the 6-nitroindazole to the hydrogen is 1 (3.0-5.0);
3) The reacted product enters a cooling module of the tubular reactor, and the temperature of the product in the cooling module is reduced to 35 ℃;
4) Collecting reaction liquid flowing out of an outlet of the cooling module, concentrating and cooling to 2 ℃, cooling and crystallizing for 3 hours, throwing materials, and carrying out forced air drying on wet products at 60 ℃ for 5 hours to obtain 6-aminoindazole;
the reaction equation for the synthesis of 6-aminoindazoles is:
the organic solvent is any one of methanol and ethanol.
The concentration of the 6-nitroindazole in the organic solvent is 0.35mol/L.
The molar ratio of the 6-nitroindazole to hydrogen is 1.
The catalyst with noble metal supported by the active carbon is any one of Pd/C and Pt/C.
The total mass of the noble metal accounts for 5-10% of the total mass of the catalyst.
The mass ratio of the 6-nitroindazole to the catalyst is 1:0.05.
the optimal reaction temperature of the reaction module is 110 ℃.
The optimal residence time of the material I and the hydrogen in the reaction module is 30-40 s.
The invention has the positive effects that: the invention adopts a tubular reactor to complete a method for synthesizing 6-aminoindazole by catalytic hydrogenation. (1) In the aspect of environmental protection, the side reaction is less, and waste is hardly generated. (2) In the aspect of safety, the tubular reactor is adopted, the liquid holding volume is only dozens of liters to dozens of liters, hydrogen leakage can be greatly reduced under the condition of safety protection, and potential safety hazards caused by hydrogen leakage are avoided. (3) By adopting the tubular reactor, the conversion efficiency is improved by more than 100 times compared with the traditional hydrogenation reduction efficiency in the continuous operation process, the reaction time is shortened from 3 hours to 30 seconds, and the energy consumption is greatly reduced. (4) By adopting the tubular reactor, the excessive hydrogenation byproducts generated at high temperature for a long time can be effectively inhibited, and the product yield and purity are improved. (5) The solid-supported catalyst is adopted, the retention time is short, the activity of the surface structure of the catalyst is not greatly changed, the activity of the catalyst is retained to the maximum extent, and the economic cost of the catalyst is reduced. (6) The equipment occupation area is small, the operation is simple, the long-time safe and stable online production can be realized by matching with the feeding terminal of the computer operation system, the labor is reduced by 90%, the production cost is reduced, and the production economy is guaranteed.
Detailed Description
A method for synthesizing an axitinib intermediate 6-aminoindazole by using a tubular reactor, wherein the 6-aminoindazole is synthesized by the following steps:
1) Mixing a raw material 6-nitroindazole and an organic solvent to obtain a material I, conveying the material I to a preheating module of a tubular reactor through a flow pump, and preheating the material I in the preheating module; the concentration of the 6-nitroindazole in the organic solvent is 0.1-0.5mol/L;
2) The preheated material I enters a reaction module of a tubular reactor, the reaction module is immobilized with active carbon to load a noble metal catalyst, and the mass ratio of the 6-nitroindazole to the catalyst is 1 (0.01-0.10); hydrogen is conveyed to a reaction module of the tubular reactor through a flow pump, the hydrogen and a material I react in the reaction module, the reaction temperature is 80-140 ℃, the reaction pressure is 0.1-1.0 MPa, the residence time of the material I and the hydrogen in the reaction module is 20-50 s, and the molar ratio of the 6-nitroindazole to the hydrogen is 1 (3.0-5.0);
3) The reacted product enters a cooling module of the tubular reactor, and the temperature of the product in the cooling module is reduced to 35 ℃;
4) Collecting reaction liquid flowing out of an outlet of the cooling module, concentrating and cooling to 2 ℃, cooling and crystallizing for 3 hours, throwing materials, and carrying out forced air drying on wet products at 60 ℃ for 5 hours to obtain 6-aminoindazole;
the reaction equation for the synthesis of 6-aminoindazoles is:
the organic solvent is any one of methanol and ethanol.
The concentration of the 6-nitroindazole in the organic solvent is 0.35mol/L.
The molar ratio of the 6-nitroindazole to hydrogen is 1.
The catalyst with noble metal supported by the active carbon is any one of Pd/C and Pt/C.
The total mass of the noble metal accounts for 5-10% of the total mass of the catalyst.
The mass ratio of the 6-nitroindazole to the catalyst is 1:0.05.
the optimal reaction temperature of the reaction module is 110 ℃.
The optimal residence time of the material I and the hydrogen in the reaction module is 30-40 s.
Example 1:
weighing 45kg of raw material 6-nitroindazole and 1000L of absolute ethyl alcohol, mixing to obtain a material I, and conveying the material I to a preheating module of a tubular reactor through a flow pump for preheating. Adjusting the flow rate of the flow pump to make the flow rate of the material I be 30.0kg/min, and adjusting H 2 The flow rate of a gas flowmeter is 75g/min, the molar ratio of the raw material 6-nitroindazole to hydrogen is 1.
Example 2:
weighing 45kg of raw material 6-nitroindazole and 1000L of anhydrous methanol, mixing to obtain a material I, and conveying the material I to a preheating module of a tubular reactor through a flow pump for preheating. Adjusting the flow rate of the flow pump to make the flow rate of the material I be 30.0kg/min, and adjusting H 2 The flow rate of a gas flow meter is 75g/min, the molar ratio of the raw material 6-nitroindazole to hydrogen is 1.
Example 3:
weighing 45kg of raw material 6-nitroindazole and 1000L of absolute ethyl alcohol, mixing to obtain a material I, and conveying the material I to a preheating module of a tubular reactor through a flow pump for preheating. Adjusting the flow rate of the flow pump to make the flow rate of the material I be 30.0kg/min, and adjusting H 2 The flow rate of a gas flowmeter is 56g/min, the molar ratio of the raw material 6-nitroindazole to hydrogen is 1. And (3) analysis: the molar ratio of the starting 6-nitroindazole to hydrogen is 1: at 3.0, the reaction was incomplete and some of the 6-nitroindazole was not reacted.
Example 4:
weighing 45kg of raw material 6-nitroindazole and 1000L of absolute ethyl alcohol, mixing to obtain a material I, and conveying the material I to a preheating module of a tubular reactor through a flow pump for preheating. Adjusting the flow rate of the flow pump to make the flow rate of the material I be 30.0kg/min, and adjusting H 2 The flow rate of the gas flow meter was 75g/min, the molar ratio of the starting 6-nitroindazole to hydrogen was 1The temperature of the reaction is 35 ℃, the reaction retention time is 35s, the reaction pressure is 0.1MPa, the reaction liquid flowing out from the outlet of the cooling module is collected, concentrated and cooled to 2 ℃, cooled and crystallized for 3 hours, the material is thrown off, and the wet product is dried by air blowing at 60 ℃ for 5 hours to obtain 33.68kg of 6-aminoindazole, the yield is 93.71 percent, and the content is 95.54 percent.
Example 5:
weighing 45kg of raw material 6-nitroindazole and 1000L of absolute ethyl alcohol, mixing to obtain a material I, and conveying the material I to a preheating module of a tubular reactor through a flow pump for preheating. The flow rate of the flow pump is adjusted to make the flow rate of the material I be 30.0kg/min, and H is adjusted 2 The flow rate of the gas flow meter is 66g/min, the molar ratio of the raw material 6-nitroindazole to hydrogen is 1.
Investigation of reaction temperature:
in order to examine the influence of the reaction temperature on the yield and the purity, the influence of the reaction temperature of 80 ℃,90 ℃,100 ℃,120 ℃ and 130 ℃ on the reaction result is respectively examined, and the specific method comprises the following steps:
example 6, this example differs from example 1 in that: the reaction temperature described in this example was 80 ℃.
Example 7, this example differs from example 1 in that: the reaction temperature described in this example was 90 ℃.
Example 8, this example differs from example 1 in that: the reaction temperature described in this example was 100 ℃.
Example 9, this example differs from example 1 in that: the reaction temperature described in this example was 120 ℃.
Example 10, this example differs from example 1 in that: the reaction temperature described in this example was 130 ℃.
| Experimental group | Reaction temperature | Yield of the product | Purity of |
| Example 6 | 80℃ | 93.68% | 98.67% |
| Example 7 | 90℃ | 94.12% | 99.04% |
| Example 8 | 100℃ | 94.13% | 98.78% |
| Example 1 | 110℃ | 96.8% | 99.54% |
| Example 9 | 120℃ | 95.48% | 99.49% |
| Example 10 | 130℃ | 95.96% | 98.15% |
As can be seen from the above table, the reaction temperature has a great influence on the yield and purity of the target product, the reaction temperature is low, the yield is low, the reaction temperature is too high, excessive hydrogenation and pyrolysis are caused, and a large amount of byproducts are generated. In view of this, the reaction temperature is preferably 110 ℃.
Investigation of reaction residence time:
in order to investigate the influence of the reaction temperature on the yield and the purity and respectively investigate the influence of different reaction residence times on the reaction result, the specific method is as follows:
example 11, this example differs from example 1 in that: the reaction residence time described in this example was 20s.
Example 12, this example differs from example 1 in that: the reaction residence time described in this example was 25s.
Example 13, this example differs from example 1 in that: the reaction residence time described in this example was 30s.
Example 14, this example differs from example 1 in that: the reaction residence time described in this example was 40s.
Example 15, this example differs from example 1 in that: the reaction residence time described in this example was 45s.
Example 16, this example differs from example 1 in that: the reaction residence time described in this example was 50s.
| Experiment of the inventionGroup(s) | Residence time of the reaction | Yield of | Purity of |
| Example 11 | 20s | 90.34% | 98.13% |
| Example 12 | 25s | 92.65% | 98.22% |
| Example 13 | 30s | 95.87% | 99.51% |
| Example 1 | 35℃ | 96.80% | 99.54% |
| Example 14 | 40s | 96.69% | 99.11% |
| Example 15 | 45s | 95.68% | 98.35% |
| Example 16 | 50s | 95.24% | 98.42% |
As can be seen from the above table, the reaction residence time has a great influence on the yield and purity of the target product, when the reaction residence time is between 30 and 40s, the acceptance and purity of the product are relatively ideal, and the reaction is influenced by too long or too short reaction time. Therefore, the reaction time is most reasonably kept between 30 and 40 seconds.
Investigation of the number of times of application of the immobilized catalyst:
in order to examine the recycling efficiency of the catalyst, on the basis of example 1, the influence of the recycling frequency of the catalyst of the noble metal loaded on the activated carbon on the reaction yield and the reaction purity is mainly examined. The specific method comprises the following steps: taking activated carbon supported noble metal as a catalyst, and carrying out 10 times of cyclic application experiments, namely: the Pd/C catalyst is used in the first experiment in the example 1, then the reaction is carried out again under the same experiment conditions, and the like, and the experiment is carried out for 10 times of cyclic application; the experiment for each application is carried out according to the example 1, and the experimental process and the reaction conditions of the immobilized catalyst are kept consistent each time.
The results of the cyclic application experiment are as follows:
| number of times of applying the supported catalyst | Yield of | Purity of |
| 0 | 96.80% | 99.54% |
| 1 | 96.21% | 99.62% |
| 2 | 96.45% | 99.39% |
| 3 | 96.30% | 99.32% |
| 4 | 96.27% | 99.12% |
| 5 | 96.08% | 99.36% |
| 6 | 96.43% | 99.61% |
| 7 | 96.05% | 99.35% |
| 8 | 95.92% | 99.30% |
| 9 | 95.63% | 99.41% |
| 10 | 95.57% | 99.23% |
As can be seen from the above table, the conversion rate and product purity of the Pd/C supported catalyst used repeatedly do not decrease significantly, which indicates that the supported catalyst still has high reaction activity after 10 times of use.
In conclusion, the method for synthesizing the axitinib intermediate 6-aminoindazole by adopting the tubular reactor has production value in consideration of various factors such as safety, environmental protection, product yield, product purity, reaction time and the like.
Claims (9)
1. A method for synthesizing an axitinib intermediate 6-aminoindazole by using a tubular reactor is characterized by comprising the following steps:
the 6-aminoindazole is synthesized by the following steps:
1) Mixing a raw material 6-nitroindazole and an organic solvent to obtain a material I, conveying the material I to a preheating module of a tubular reactor through a flow pump, and preheating the material I in the preheating module; the concentration of the 6-nitroindazole in the organic solvent is 0.1-0.5mol/L;
2) The preheated material I enters a reaction module of a tubular reactor, the reaction module is immobilized with active carbon to load a noble metal catalyst, and the mass ratio of the 6-nitroindazole to the catalyst is 1 (0.01-0.10); hydrogen is conveyed to a reaction module of the tubular reactor through a flow pump, the hydrogen and a material I react in the reaction module, the reaction temperature is 80-140 ℃, the reaction pressure is 0.1-1.0 MPa, the residence time of the material I and the hydrogen in the reaction module is 20-50 s, and the molar ratio of the 6-nitroindazole to the hydrogen is 1 (3.0-5.0);
3) The reacted product enters a cooling module of the tubular reactor, and the temperature of the product in the cooling module is reduced to 35 ℃;
4) Collecting reaction liquid flowing out of an outlet of the cooling module, concentrating and cooling to 2 ℃, cooling and crystallizing for 3 hours, throwing materials, and carrying out forced air drying on wet products at 60 ℃ for 5 hours to obtain 6-aminoindazole;
the reaction equation for the synthesis of 6-aminoindazoles is:
2. the tubular reactor synthesis of an axitinib intermediate 6-aminoindazole according to claim 1, characterized in that: the organic solvent is any one of methanol and ethanol.
3. The tubular reactor synthesis method of the acitinib intermediate 6-aminoindazole according to claim 1, characterized in that: the concentration of the 6-nitroindazole in the organic solvent is 0.35mol/L.
4. The tubular reactor synthesis method of the acitinib intermediate 6-aminoindazole according to claim 1, characterized in that: the molar ratio of the 6-nitroindazole to hydrogen is 1.
5. The tubular reactor synthesis of an axitinib intermediate 6-aminoindazole according to claim 1, characterized in that: the catalyst with noble metal supported by the active carbon is any one of Pd/C and Pt/C.
6. The tubular reactor synthesis method of the acitinib intermediate 6-aminoindazole according to claim 1 or 5, characterized in that: the total mass of the noble metal accounts for 5-10% of the total mass of the catalyst.
7. The tubular reactor synthesis method of the acitinib intermediate 6-aminoindazole according to claim 1, characterized in that: the mass ratio of the 6-nitroindazole to the catalyst is 1:0.05.
8. the tubular reactor synthesis of an axitinib intermediate 6-aminoindazole according to claim 1, characterized in that: the optimal reaction temperature of the reaction module is 110 ℃.
9. The tubular reactor synthesis of an axitinib intermediate 6-aminoindazole according to claim 1, characterized in that: the optimal residence time of the material I and the hydrogen in the reaction module is 30-40 s.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006071940A2 (en) * | 2004-12-23 | 2006-07-06 | Deciphera Pharmaceuticals, Llc | Enzyme modulators and treatments |
| CN107089969A (en) * | 2017-04-26 | 2017-08-25 | 黑龙江鑫创生物科技开发有限公司 | A kind of method for synthesizing imatinib intermediate |
| CN108017575A (en) * | 2018-01-26 | 2018-05-11 | 黑龙江鑫创生物科技开发有限公司 | A kind of method that micro passage reaction synthesis gram azoles replaces Buddhist nun's intermediate |
| CN108329314A (en) * | 2018-04-16 | 2018-07-27 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Eliquis intermediate |
| CN108484579A (en) * | 2018-03-28 | 2018-09-04 | 黑龙江鑫创生物科技开发有限公司 | A kind of micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand |
| CN108689964A (en) * | 2018-05-21 | 2018-10-23 | 黑龙江鑫创生物科技开发有限公司 | A kind of micro passage reaction synthesizes the method that more Weis replace Buddhist nun's intermediate |
-
2022
- 2022-10-17 CN CN202211267121.3A patent/CN115504937A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006071940A2 (en) * | 2004-12-23 | 2006-07-06 | Deciphera Pharmaceuticals, Llc | Enzyme modulators and treatments |
| CN107089969A (en) * | 2017-04-26 | 2017-08-25 | 黑龙江鑫创生物科技开发有限公司 | A kind of method for synthesizing imatinib intermediate |
| CN108017575A (en) * | 2018-01-26 | 2018-05-11 | 黑龙江鑫创生物科技开发有限公司 | A kind of method that micro passage reaction synthesis gram azoles replaces Buddhist nun's intermediate |
| CN108484579A (en) * | 2018-03-28 | 2018-09-04 | 黑龙江鑫创生物科技开发有限公司 | A kind of micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand |
| CN108329314A (en) * | 2018-04-16 | 2018-07-27 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Eliquis intermediate |
| CN108689964A (en) * | 2018-05-21 | 2018-10-23 | 黑龙江鑫创生物科技开发有限公司 | A kind of micro passage reaction synthesizes the method that more Weis replace Buddhist nun's intermediate |
Non-Patent Citations (1)
| Title |
|---|
| OSCAR VERHO等: "Mild and Selective Hydrogenation of Nitro Compounds using Palladium Nanoparticles Supported on Amino- Functionalized Mesocellular Foam", 《CHEMCATCHEM》, no. 6, pages 3153 * |
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