CN107382983B - Synthesis method of medicine for treating leukemia - Google Patents
Synthesis method of medicine for treating leukemia Download PDFInfo
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- CN107382983B CN107382983B CN201710736325.XA CN201710736325A CN107382983B CN 107382983 B CN107382983 B CN 107382983B CN 201710736325 A CN201710736325 A CN 201710736325A CN 107382983 B CN107382983 B CN 107382983B
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Abstract
The invention relates to a synthesis method of a medicament for treating leukemia, which comprises the following steps of 1, reacting a compound 3-methyl-3-oxetane methanol with metallic sodium to obtain 3-sodium methoxide-3-methyl-oxetane; step 2, adding 4-amino-3-nitrochlorobenzene into the product of the step 1 to obtain a red orange solid (A1); reacting the compound 8-benzyloxy quinoline-2-chlorine with A1 to obtain an orange solid A2; step 3, reacting the compound A2 with 13g of palladium/carbon and formic acid, adding formamidine acetate, refluxing and drying to obtain a white (or yellow) solid A3; step 4, reacting the compound A3 with trifluoromethyl sulfonyl chloride and drying to obtain a beige solid A4; BINAP reacts with A4, piperidine-4-yl tert-butyl carbamate and potassium carbonate, and is dried to obtain A5; a5 is refined in step 5 to obtain the pure product. Wherein 1 and 2 are one-pot processes.
Description
The technical field is as follows:
the invention relates to preparation of a pharmaceutical compound, in particular to a synthesis method of an anticancer drug.
Background art:
although large-dose chemotherapy and the like can benefit patients in a short term, most patients can suffer from disease relapse, and the effect of the subsequent large-dose chemotherapy is always poor regardless of disease relapse or difficult treatment, and selectable treatment strategies are very limited, so that the problem of poor prognosis is solved.
Crenolanib, the structural formula is as follows:
the compound is an effective and selective PDGFR α/β inhibitor, can inhibit the activity of PDGFR α kinase (D842I, D842V, D842Y, D1842-843IM, and deletion I843) resistant to imatinib, can be used for treating various cancers, including acute myelogenous leukemia, gastrointestinal stromal tumors, glioma, non-small cell lung cancer and the like, the Crenolanib acts on D842V in an isogenic model system and is 135-fold more effective than imatinib, the IC50 is about 10nM, the Crenolanib inhibits the kinase activity of fusion oncogenes in EO L-1 cells, is derived from chronic eosinophilic cremopathy crecytic crewaemia patients, and expresses FIP 1L-PDGFR α fusion which is continuously activated, the IC50 is 21nM, the IC 6384 is 21nM, the IC nonlianib also inhibits the proliferation of EO L-1 cells, the IC50 is 0.2pM, the PDG is capable of inhibiting the proliferation of PDGFR 5632-21 nM, the PDGF is capable of inhibiting the PDGF α -1-CD kinase activity of TK kinase in the cancer cell line which is equivalent to TK-19 nM, the HIV 4624 nM, the HIV 4617 is capable of inhibiting the growth of the HIV 19-5-19-5-rat, the lung cancer cell line, the PDG-activating factor of the TK kinase, and the TK kinase which are respectively, and the lung cancer cell line.
Because the medicine has good treatment prospect, a great deal of research is carried out on the synthesis of the medicine. Wherein the route for the synthesis of this compound in WO2004/113322 is as follows:
a related synthetic route to WO2004/020431 is as follows:
the above process route involves some unusual and expensive reagents such as: n-phenyl-bis (trifluoromethanesulfonimide), tris (dibenzylideneacetone) dipalladium, 4, 5-bis (diphenylphosphino) -9, 9-dimethyl tricyclic dibenzo ligand (Xantphos), flammable and explosive sodium hydride, boron tribromide with high toxicity, high corrosivity and explosive toxicity, and the like, and a mixed solvent is used, so that the recovery is not easy, unnecessary pollution to the environment is easily caused, and the factors are not suitable for industrial production. Therefore, it is necessary to find an industrial preparation method with simple operation, safety, environmental protection, high yield and purity and low production cost.
Therefore, the method provides the Crenolanib which is prepared by taking 3-methyl-3-oxetanemethanol as an initial raw material and carrying out esterification, two-step condensation, reduction ring closing, esterification, substitution, deprotection and salt formation.
Disclosure of Invention
The invention aims to provide a preparation method of a potential medicine for treating acute myeloid leukemia, which overcomes the defects of the prior art, has the advantages of simple operation, safety, environmental protection, high yield and purity and low production cost, and is particularly suitable for mass preparation and industrial production.
To achieve the object of the present invention, the following embodiments are provided:
a method for synthesizing Crenolanib, comprising the steps of:
the preparation method is characterized in that 3-methyl-3-oxetanemethanol is used as a starting material and is prepared through the following steps.
Step 1, substitution:
in the step 2, palladium acetate is used for replacing expensive tris (dibenzylidene acetone) dipalladium which is difficult to synthesize, so that the yield is improved by 19 percent, and the reaction time is shortened.
Wherein the inorganic base is selected from: cesium carbonate, sodium hydroxide, potassium hydroxide, and the like.
The original process uses formaldehyde and palladium hydroxide to reduce nitro, then uses palladium carbon to remove benzyl, and the improvement is that formic acid and palladium carbon system is used to reduce nitro, and at the same time remove benzyl, the yield is raised by 13.36%
Step 3, closing the ring
Step 4, esterification, substitution
In the substitution step, 4, 5-bis (diphenylphosphino) -9, 9-dimethyl tricyclic dibenzo ligand (Xantphos) is used originally, but the product purity is poor, the yield is low, BINAP is used as a ligand catalyst, and the yield is improved by 17%;
and 5, refining. The original process uses a large amount of water and organic mixed solvent, is not easy to recover, generates a large amount of inorganic and organic waste liquid, and adopts a salt-forming alkali-returning method after improvement, thereby greatly reducing the production cost.
Preferably, the method of the invention is as follows:
step 1, substitution: reacting the compound 3-methyl-3-oxetanyl methanol with metallic sodium to obtain 3-sodium methoxide-3-methyl-oxetane;
Reacting the compound 8-benzyloxy quinoline-2-chlorine with A1 to obtain an orange solid A2;
step 3 preparation of 2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-ol (A3)
Reacting compound A2 with palladium/carbon 13g in formic acid, adding formamidine acetate, refluxing and drying to obtain a white (or yellow) solid A3;
step 4 preparation of trifluoro-methanesulfonic acid-2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl ester (A4)
Reacting the compound A3 with trifluoromethyl sulfonyl chloride, and drying to obtain a beige solid A4;
preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl) -carbamic acid tert-butyl ester (A5)
BINAP reacts with A4, piperidine-4-base tert-butyl carbamate and potassium carbonate, and is dried to obtain orange yellow solid A5;
preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-ylamine (A6)
Heating the compound A5, sodium ethoxide and 2-methyltetrahydrofuran to reflux, filtering, crystallizing and drying to obtain a light yellow solid A6;
step 5, refining the mixture,
weighing an A6 crude product, dissolving the crude product in ethanol, adding benzenesulfonic acid, refluxing and drying, adding the dried solid into water, adjusting the pH value to 10-12 by using 1 sodium hydroxide, adding dichloromethane for extraction, filtering an organic phase, filtering the solid, and concentrating the filtrate under reduced pressure; the obtained oily matter is dried to obtain solid which is the finished product.
Particularly preferably, the process of the invention is as follows:
step 1, sodium alkoxide: reacting the compound 3-methyl-3-oxetanyl methanol with metal sodium to obtain 3-methylsulfonyl-3-methyl-oxetane;
preparation of (8-benzyloxy-quinolin-2-yl) - [4- (3-methyl-oxetan-3-ylmethoxy) -2-nitro-phenyl ] -amine (A2)
Uniformly stirring a compound 8-benzyloxy quinoline-2-chlorine, A1, potassium carbonate, DIPHOS, toluene and palladium acetate, reacting, and removing benzyl to obtain an orange solid A2;
step 3, preparation of ring-closed, 2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-ol (A3)
Reacting compound A2 with palladium/carbon 13g in formic acid, adding formamidine acetate, refluxing and drying to obtain a white (or yellow) solid A3;
step 4, preparation of esterified, substituted, trifluoro-methanesulfonic acid-2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl ester (A4)
Reacting the compound A3 with trifluoromethyl sulfonyl chloride, and drying to obtain a beige solid A4;
preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl) -carbamic acid tert-butyl ester (A5)
BINAP reacts with A4, piperidine-4-base tert-butyl carbamate and potassium carbonate, and is dried to obtain orange yellow solid A5;
preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-ylamine (A6)
Heating the compound A5, sodium ethoxide and 2-methyltetrahydrofuran to reflux, filtering, crystallizing and drying to obtain a light yellow solid A6;
step 5, refining the mixture,
weighing an A6 crude product, dissolving the crude product in ethanol, adding benzenesulfonic acid, refluxing and drying, adding the dried solid into water, adjusting the pH value to 10-12 by using 1 sodium hydroxide, adding dichloromethane for extraction, filtering an organic phase, filtering the solid, and concentrating the filtrate under reduced pressure; the obtained oily matter is dried to obtain solid which is the finished product.
The method can synthesize the final product under relatively mild and cheap conditions. Compared with the prior art, the method has the advantages of simple process, high product purity, high yield, short process, easily available and cheap materials, low cost, safe operation, and high total yield which is greatly higher than that of the prior art, and is more favorable for industrial production.
The improvement of the present invention is made because the prior art has the following drawbacks:
the reaction activity of the corresponding sulfonate is improved, but the generated sulfonate is a pungent chemical raw material due to the fact that the p-toluenesulfonyl chloride or the methanesulfonyl chloride is a genetic toxic material which is verified in the pharmaceutical field, and potential hidden danger is possibly brought to the quality of a final product.
2. In the condensation stage, the prior art uses expensive tris (dibenzylideneacetone) dipalladium, and the yield is not high;
3. the method adopts formaldehyde and palladium hydroxide to reduce nitro, and then uses palladium carbon to remove benzyl, so that the steps are relatively complex;
4. in the substitution step, an expensive 4, 5-bis (diphenylphosphino) -9, 9-dimethyltricyclic dibenzo ligand (Xantphos) is used, which increases the cost and leads to poor product purity and low yield
5. In the refining stage, a large amount of water and organic mixed solvent is used in the prior art, so that the solvent is not easy to recover, a large amount of organic waste liquid is generated, and unnecessary pollution is easily brought to the environment.
In order to better embody the characteristics of green, environmental protection, low cost and the like after improvement, necessary screening is carried out on the technical defects through the following scheme, which is detailed in the embodiment, wherein the specific screening process is as follows:
1. preparation of intermediate A1
Due to the defects of toxicity, genetic toxicity, irritation and the like of the materials, and due to the fact that the cyclic ether exists in the structure of the starting material 3-methyl-3-oxetanemethanol and is unstable to acidity, a williamson ether synthesis method is adopted, and therefore the defects of the prior art can be well avoided.
As THF in the examples, benzene, toluene, xylene, nitrobenzene, acetonitrile, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and the like can be used, and a low boiling solvent such as THF is preferably used. The reaction temperature is 50-70 deg.C, preferably 60-66 deg.C.
2. Preparation of intermediate A2
Palladium acetate is used for replacing expensive tris (dibenzylideneacetone) dipalladium which is difficult to synthesize, so that the yield is improved by 19 percent, and the reaction time is shortened.
The catalyst in the examples is not limited to palladium acetate, such as: tetrakis (triphenylphosphine) palladium, diphenylphosphinoferrocene palladium dichloride, dichlorodiphenylphosphine palladium, palladium carbon and palladium are attached to carrier catalysts such as alumina, calcium carbonate, barium sulfate and the like. Palladium acetate is preferred in this example, and reaction selectivity and reaction conversion rate can be improved.
3. Preparation of intermediate A3
The original process uses formaldehyde and palladium hydroxide to reduce nitro, and then uses palladium carbon to remove benzyl, the improvement is that formic acid and palladium carbon system is used to reduce nitro, and simultaneously remove benzyl, the yield is increased by 13.36%.
Examples of catalysts, not limited to palladium on carbon, such as: palladium hydroxide and palladium are attached to various metal salts such as alumina, silica, diatomaceous earth, etc. Palladium on carbon is preferred because it can promote the reaction better and can play an important role in deprotecting the group.
4. Preparation of intermediate A4
In the substitution step, 4, 5-bis (diphenylphosphino) -9, 9-dimethyl tricyclic dibenzo ligand (Xantphos) was used originally, but the product purity was poor and the yield was low, and BINAP was used as a ligand catalyst.
The catalysts employed in the examples are not limited to BINAP ligand catalysts such as: 2-dicyclohexylphosphine-2-2 ', 4 ', 6 ' -triisopropylbiphenyl, 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl, 2-dicyclohexylphosphine-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl, 4,5 ' -bis-diphenylphosphino-9, 9-dimethylxanthene, 1 ' -bis (diphenylphosphino) ferrocene, 1 ' -binaphthol, (±) -2,2 ' -bis- (diphenylphosphino) -1,1 ' -binaphthyl, tricyclohexylphosphine, and the like. Wherein BINAP is used as ligand catalyst, which can obviously improve the reaction yield.
5. Preparation of intermediate A5
The prior art refines the product by using a large amount of water and organic mixed solvent, is not easy to recover, generates a large amount of organic waste liquid, and can achieve the aim by adopting a conventional crystallization method after improvement.
It has been found by screening that the above-mentioned drawbacks of the prior art can be overcome with the solution of the invention.
For experimental data on advantages see the examples below:
description of the drawings:
FIG. 1H NMR of the end product
The specific implementation mode is as follows:
the invention is further illustrated by the following examples.
Examples
Preparation of 4 (3-methyl-oxetan-3-ylmethoxy) -2-nitro-phenylamine (A1)
Adding 28g of compound 3-methyl-3-oxetanemethanol, 140ml of THF (tetrahydrofuran), 140ml g of metal sodium and 6.32g of metal sodium into a 250ml three-necked bottle, heating to 66 ℃ under stirring for refluxing for 4h, cooling to 55 ℃, adding 40.4g of 4-amino-3-nitrochlorobenzene, heating under stirring, controlling the temperature to be 50-60 ℃ for reacting for 24h, adding 180ml of ethyl acetate into the reaction bottle, stirring at 35-40 ℃ for 0.5h, filtering, washing a filter cake with 180ml of x2, washing the filtrate with 500ml of 0.5N sodium hydroxide and saturated sodium chloride solution respectively, drying an organic phase with 30g of anhydrous magnesium sulfate for 0.5h, filtering out a drying agent, concentrating the filtrate under reduced pressure, adding 140ml of isopropanol to the concentrated residue, stirring for 10h at 15-20 ℃, filtering the precipitated solid, and drying by blowing at 40 ℃ to obtain 45.28g of a red orange solid with the yield of 75.3%.
Preparation of (8-benzyloxy-quinolin-2-yl) - [4- (3-methyl-oxetan-3-ylmethoxy) -2-nitro-phenyl ] -amine (A2)
Adding 47.2g of compound 8-benzyloxyquinoline-2-chlorine, A150 g, 80g of potassium carbonate, 4.3g of DIPHOS and 700ml of methylbenzene into a 2L three-necked bottle, adding 0.9g of palladium acetate, uniformly stirring, heating while stirring, controlling the temperature to 98-100 ℃ to react for 24-30 h, after the reaction is finished, cooling to 55 ℃, adding 700ml of dichloroethane, stirring for 10min, adding kieselguhr to filter solids in the reaction solution, washing a filter cake with 500ml of dichloroethane, concentrating the filtrate to dryness, adding 480ml of ethyl acetate, heating to reflux, cooling to 20-25 ℃, crystallizing for 10-20 h, filtering the precipitated solids, and drying by blowing at 50 ℃ to obtain orange solids, namely A2, 79.69g of solids and 96.37 percent.
Preparation of 2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-ol (A3)
Adding the compound A265 g, 650ml of ethanol, 101.4ml of triethylamine and 13g of palladium/carbon into a 1L three-necked bottle, uniformly stirring, heating the reaction solution to 45 ℃, dropwise adding 28.6ml of formic acid, heating the reaction solution to 50-55 ℃ after dropwise adding is finished for about 40min, and reacting for 20-24 h.
T L C, detecting that the reaction is complete (a developing agent: dichloromethane), stopping heating, reducing the temperature to 40 ℃, filtering by using diatomite, washing a filter cake by using 150ml of ethanol, adding 30g of formamidine acetate into the filtrate, heating and refluxing for 8h, then cooling to 20-25 ℃, crystallizing for 10-20 h, filtering, and drying to obtain a white (or yellow) like solid A3, 47.51g and 95.36%.
Preparation of trifluoro-methanesulfonic acid-2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl ester (A4)
Compound A320 g, DMF60ml, trifluoromethylsulfonyl chloride 21.8g, and pyridine 11.2g were added to a 250ml three-necked flask and stirred well. Controlling the temperature to be 25-30 ℃ and reacting for 20-30 h. After completion of the reaction, the precipitated solid was filtered, and the filter cake was washed with DMF20ml and then with 40ml of n-hexane. And (3) drying by blowing at 40 ℃ to obtain beige solid A4,24.89g and the yield of 91.16%.
Preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl) -carbamic acid tert-butyl ester (A5)
Adding 0.8g of BINAP and 70ml of toluene into a 250ml three-necked flask, and stirring for 0.5h at the temperature of 20-25 ℃. Then, A410 g, 8.2g of tert-butyl piperidin-4-ylcarbamate and 9.4g of potassium carbonate were added to the flask, and the reaction mixture was heated to 85 ℃ with stirring, and the temperature was maintained and the reaction was carried out for 24 to 30 hours.
T L C detects whether the reaction is complete or not, stops heating after the reaction is completed, cools to 30 ℃, adds 50ml of dichloroethane, adds diatomite to filter out solids in the reaction solution, washes a filter cake with 50ml of dichloroethane, then concentrates the reaction solution to be dry, then adds 150ml of ethyl acetate, stirs for 8h at 20-25 ℃, filters out solids precipitated from the solution, washes the filtrate with 2.5% ammonia water solution 2x90ml, again concentrates the organic phase to be dry, adds 50ml of acetonitrile, stirs for crystallization for 10-20 h at 20-25 ℃, filters out the precipitated solids, and dries by air blowing at 40 ℃ to obtain orange yellow solids, namely A5, 10.41g and the yield of 94.16%.
Preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-ylamine (A6)
2g of a refined product of 5, 1.8g of sodium ethoxide, 30ml of 2-methyltetrahydrofuran and 0.08ml of water were put into a 100ml three-necked flask and stirred uniformly. The mixture is heated to reflux and stirred for 3-4 h under reflux.
T L C detection, reaction is completed, heating is stopped, 60ml of purified water is added, extraction layering is carried out, a water phase is extracted by ethyl acetate 2X20ml, an organic phase is combined, 20ml of saturated sodium chloride solution is used for washing, the organic phase is concentrated under reduced pressure, 30ml of ethyl acetate is added into concentrated residues, the mixture is stirred and crystallized at the temperature of 20-25 ℃ for 3h, the precipitated solid is filtered, the filtrate is concentrated under reduced pressure to be dry, 14ml of ethyl acetate is added into the residues, the mixture is stirred and crystallized at the temperature of 20-25 ℃ for 10h, the precipitated solid is filtered, and light yellow solid is obtained after drying, namely A6, 1,613g and the yield is 98.77%.
Purification of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-ylamine (purification of A6)
10g of crude A6 and 100ml of ethanol are weighed into a 250ml three-necked flask, and heated to reflux with stirring to dissolve the crude A6. Then cooled to room temperature, 3.8g of benzenesulfonic acid was added and heated to reflux for 0.5 h. Slowly cooling to room temperature for crystallization for 16h, filtering the precipitated solid, and drying.
Adding the dried solid into 100ml of water, adjusting the pH value to 10-12 by using 10% sodium hydroxide, and continuously stirring for 0.5 h. Dichloromethane was added for extraction 3 × 50ml and the organic phase was washed with 50ml saturated sodium chloride. To the organic phase were added 3g of anhydrous magnesium sulfate and 1g of activated carbon, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off and the filtrate was concentrated under reduced pressure. The resulting oil was added to 100ml of ethyl acetate and crystallized at room temperature for 4 hours. The precipitated solid was filtered and air-dried at 40 ℃ to obtain 9.34g of a solid as a finished product with a crystallization rate of 93.40%.
1HNMR of the end product (see the attached drawing for details)
(d6-DMSO):9.17(s,1H),8.91(d,1H,J＝8.7Hz),8.53(d,1H,J＝9.0Hz)，8.16(d,1H,J＝9.0Hz)，7.60(d,1H,J＝7.5Hz)，7.49(t,1H,J＝7.9Hz)7.29(d,1H,J＝2.4Hz)，7.27(d,1H,J＝7.6Hz)，7.19(dd,1H,J＝9.2hz,2.5Hz)4.56(d,2H,J＝5.6Hz),4.34(d,2H,J＝5.7Hz),4.15(s,2H),3.75(d,2H,J＝10.1Hz)，2.80(m,3H)，1.92(d,2H,J＝11.1Hz)，1.71(m,2H),1.41(s,3H)
The foregoing has been a detailed description of the invention including preferred embodiments thereof. It will be appreciated, however, that in view of the present disclosure, those skilled in the art can make changes and/or modifications to the present invention within the scope of the following claims, and such modifications and refinements should be considered as within the scope of the present invention.
Claims (1)
1. A method for synthesizing Crenolanib, comprising the steps of:
step 1, replacement:
step 2 condensation
Step 3, closing the ring
Step 4 esterification, substitution
The method is characterized by comprising the following steps:
a1 is prepared by adding 28g of compound 3-methyl-3-oxetanemethanol, 140ml of THF and 6.32g of sodium metal into a 250ml three-necked bottle, heating to 66 ℃ under stirring for refluxing for 4h, cooling to 55 ℃, adding 40.4g of 4-amino-3-nitrochlorobenzene, heating under stirring, controlling the temperature to react at 50-60 ℃ for 24h, adding 180ml of ethyl acetate into the reaction bottle, stirring at 35-40 ℃ for 0.5h, filtering, washing a filter cake with 180ml of x2, washing the filtrate with 500ml of 0.5N sodium hydroxide and saturated sodium chloride solution, drying an organic phase with 30g of anhydrous magnesium sulfate for 0.5h, filtering out a drying agent, concentrating the filtrate under reduced pressure, adding 140ml of isopropanol into the concentrated residue, stirring at 15-20 ℃ for 10h, filtering the precipitated solid, and drying by air blowing at 40 ℃ to obtain a reddish orange solid;
a2 is prepared by adding 47.2g of compound 8-benzyloxy quinoline-2-chlorine, 150A 150 g, 80g of potassium carbonate, 4.3g of DIPHOS and 700ml of toluene into a 2L three-necked bottle, adding 0.9g of palladium acetate, uniformly stirring, heating while stirring, controlling the temperature to 98-100 ℃ for reaction for 24-30 h, cooling to 55 ℃ after the reaction is finished, adding 700ml of dichloroethane, stirring for 10min, adding kieselguhr, filtering solids in the reaction solution, washing a filter cake with 500ml of dichloroethane, concentrating the filtrate to dryness, adding 480ml of ethyl acetate, heating to reflux, cooling to 20-25 ℃ for crystallization for 10-20 h, filtering the precipitated solids, and drying by blowing at 50 ℃ to obtain an orange solid A2;
a3 is prepared by adding compound A265 g, 650ml of ethanol, 101.4ml of triethylamine and 13g of palladium/carbon into a 1L three-necked bottle, stirring uniformly, heating the reaction solution to 45 ℃, dropwise adding 28.6ml of formic acid, heating the reaction solution for 20-24 h after 40min dropwise addition, stopping heating, cooling to 40 ℃, filtering with diatomite, washing a filter cake with 150ml of ethanol, adding 30g of formamidine acetate into the filtrate, heating for reflux for 8h, cooling to 20-25 ℃, crystallizing for 10-20 h, filtering, drying to obtain a white-like solid A3,
a4 is prepared by adding compound A320 g, DMF60ml, trifluoromethylsulfonyl chloride 21.8g and pyridine 11.2g into a 250ml three-necked flask, stirring uniformly, controlling the temperature at 25-30 ℃ to react for 20-30 h, filtering to separate out solid after the reaction is completed, washing a filter cake with DMF20ml, then washing with n-hexane 40ml, drying by blowing at 40 ℃ to obtain beige solid A4,
a5 is prepared by adding BINAP 0.8g and toluene 70ml into a 250ml three-necked bottle, stirring for 0.5h while controlling the temperature at 20-25 ℃, adding A410 g, piperidine-4-yl tert-butyl carbamate 8.2g and potassium carbonate 9.4g into the bottle, heating the reaction liquid to 85 ℃ while stirring, keeping the temperature for reaction for 24-30 h, stopping heating, cooling to 30 ℃, adding dichloroethane 50ml, adding diatomite, filtering out the solids in the reaction liquid, washing the filter cake with dichloroethane 50ml, concentrating the reaction liquid to dryness, adding ethyl acetate 150ml, stirring for 8h at 20-25 ℃, filtering out the solids precipitated from the solution, washing the filtrate with 2.5% ammonia water solution 2x90ml, concentrating the organic phase to dryness, adding acetonitrile 50ml, stirring for crystallization for 10-20 h at 20-25 ℃, filtering out the precipitated solids, blowing and drying at 40 ℃ to obtain orange yellow solids, namely A5,
a6 is prepared by adding 2g refined product A5, 1.8g sodium ethoxide, 30ml 2-methyl tetrahydrofuran and 0.08ml water into a 100ml three-necked bottle, stirring uniformly, heating the mixture to reflux, stirring for 3-4 h under reflux, detecting by T L C, reacting completely, stopping heating, adding 60ml purified water, extracting for layering, extracting the water phase with ethyl acetate 2X20ml, combining the organic phases, washing with 20ml saturated sodium chloride solution, concentrating the organic phase under reduced pressure, adding 30ml ethyl acetate into the concentrated residue, stirring for crystallization for 3h at 20-25 ℃, filtering the precipitated solid, concentrating the filtrate under reduced pressure to dryness, adding 14ml ethyl acetate into the residue, stirring for crystallization for 10h at 20-25 ℃, filtering the precipitated solid, drying to obtain a light yellow solid A6,
and A6 purification, namely weighing 10g of crude A6 and 100ml of ethanol, adding the crude A6 and the 100ml of ethanol into a 250ml three-necked bottle, heating the mixture to reflux and dissolve the crude A6 and the ethanol to the clear solution under stirring, then cooling the mixture to room temperature, adding 3.8g of benzenesulfonic acid, heating the mixture to reflux for 0.5h, slowly cooling the mixture to the room temperature for crystallization for 16h, filtering the precipitated solid, drying the dried solid, adding the dried solid into 100ml of water, adjusting the pH value to 10-12 by using 10% sodium hydroxide, continuing stirring the mixture for 0.5h, adding ethyl acetate 3x50ml for extraction, washing an organic phase by using 50ml of saturated sodium chloride, adding 3g of anhydrous magnesium sulfate and 1g of activated carbon into the organic phase, stirring the mixture at the room temperature for 1h, filtering the solid, concentrating the filtrate under reduced pressure, adding 100ml of ethyl acetate into the obtained oily substance, crystallizing the.
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| CN1402721A (en) * | 1999-11-30 | 2003-03-12 | 辉瑞产品公司 | Benzoimidazole derivs. useful as antiproliferative agents |
| CN1678604A (en) * | 2002-08-28 | 2005-10-05 | 辉瑞产品公司 | Novel benzoimidazole derivatives useful as antiproliferative agents |
| CN1809556A (en) * | 2003-06-24 | 2006-07-26 | 辉瑞产品公司 | Processes for the preparation of 1-[(benzoimidazole-1yl) quinolin-8-yl] piperidin-4-ylamine derivatives |
| CN102690194A (en) * | 2011-03-24 | 2012-09-26 | 上海通远生物科技有限公司 | Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid |
| CN103655563A (en) * | 2012-09-26 | 2014-03-26 | 安罗格制药有限责任公司 | Method of inhibiting mutant C-KIT |
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| CN1402721A (en) * | 1999-11-30 | 2003-03-12 | 辉瑞产品公司 | Benzoimidazole derivs. useful as antiproliferative agents |
| CN1678604A (en) * | 2002-08-28 | 2005-10-05 | 辉瑞产品公司 | Novel benzoimidazole derivatives useful as antiproliferative agents |
| CN1809556A (en) * | 2003-06-24 | 2006-07-26 | 辉瑞产品公司 | Processes for the preparation of 1-[(benzoimidazole-1yl) quinolin-8-yl] piperidin-4-ylamine derivatives |
| CN102690194A (en) * | 2011-03-24 | 2012-09-26 | 上海通远生物科技有限公司 | Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid |
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