CN107382984B - Preparation method of medicine for treating leukemia - Google Patents
Preparation method of medicine for treating leukemia Download PDFInfo
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- CN107382984B CN107382984B CN201710737112.9A CN201710737112A CN107382984B CN 107382984 B CN107382984 B CN 107382984B CN 201710737112 A CN201710737112 A CN 201710737112A CN 107382984 B CN107382984 B CN 107382984B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/32—Esters
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a preparation method of a medicament for treating leukemia, which comprises the following steps of 1: preparation of 2-chloro-8-trifluoromethanesulfonic quinoline step 2: preparation of tert-butyl 2-chloro-8 (piperidin-4-yl) quinolinecarboxylate step 3: preparation of 5- (3-methyloxetane-3-methoxy) benzimidazole step 4: preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester step 5 preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -4-aminopiperidine.
Description
The technical field is as follows:
the invention relates to preparation of a pharmaceutical compound, in particular to a preparation 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 routes, in part, involve the formation of sulfonic acid esters from methanesulfonyl chloride with 3-methyl-3-oxetanemethanol, which is a potentially genotoxic impurity, and thus may result in the final product containing a small or trace amount of sulfonic acid ester, which may pose a certain risk to patients. Further processes involve 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 invention provides a novel preparation method of Crenolanib.
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 producing Crenolanib, comprising the steps of:
step 1, 2-chloro-8-trifluoromethanesulfonic acid quinoline preparation
Step 2, preparation of 2-chloro-8 (piperidin-4-yl) quinolinecarboxylic acid tert-butyl ester
Step 3, preparation of 5- (3-Methyloxetane-3-methoxy) benzimidazole
Step 4 preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester
The present invention further includes the following intermediate compounds of the present invention:
preferably, the method of the invention is as follows:
step 1: preparation of 2-chloro-8-trifluoromethanesulfonic benzimidazole
Reacting 2-chloro-8-hydroxyquinoline with trifluoromethanesulfonyl chloride, filtering and drying to obtain a white solid 2-chloro-8-trifluoromethanesulfonyl benzimidazole;
step 2: preparation of tert-butyl 2-chloro-8 (piperidin-4-yl) benzimidazolecarboxylate
BINAP, 2-chloro-8-trifluoromethanesulfonic quinoline and tert-butyl piperidin-4-ylcarbamate are mixed and stirred to react, and yellow solid tert-butyl 2-chloro-8 (piperidin-4-yl) benzimidazole carbamate is obtained through filtration and drying; and step 3: preparation of 5- (3-methyloxetane-3-methoxy) benzimidazole
3-methyl-3-oxetanyl alcohol and 5-hydroxybenzimidazole react to obtain light yellow solid;
and 4, step 4: preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester
Adding palladium acetate into the products obtained in the step 2 and the step 3 for reaction, and filtering and drying to obtain a white solid;
and 5: preparation of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -4-aminopiperidine
And 4, carrying out deprotection reaction on the compound obtained in the step 4, filtering and drying to obtain a white solid.
Particularly preferably, the process of the invention is as follows:
step 1: synthesis of 2-chloro-8-triflate quinoline (I)
Reacting the compound 2-chloro-8-hydroxyquinoline with trifluoromethanesulfonyl chloride at 25-30 ℃ for 20-30 h. After the reaction is completed, filtering the precipitated solid, and drying to obtain a white-like solid;
step 2: synthesis of tert-butyl 2-chloro-8 (piperidin-4-yl) quinolinecarbamate (II)
BINAP and toluene are stirred uniformly, 2-chloro-8-trifluoromethanesulfonic quinoline and tert-butyl piperidin-4-ylcarbamate are added, the reaction solution is heated to 80-100 ℃ under stirring, the temperature is kept for reaction for 20-30 h, the reaction is complete, and yellow solid 2-chloro-8 (piperidin-4-yl) benzimidazole tert-butyl carbamate is obtained after post-treatment;
and step 3: synthesis of 5- (3-methyloxetane-3-methoxy) benzimidazole (III)
Heating and refluxing a compound 3-methyl-3-oxetanyl carbinol and 5-hydroxybenzimidazole for 20-24 hours under stirring, and carrying out aftertreatment to obtain a light yellow solid;
and 4, step 4: synthesis of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester (IV)
Adding palladium acetate into the compound II, controlling the temperature to be 80-100 ℃ and reacting for 24-30 h, and after the reaction is finished, carrying out post-treatment to obtain a white solid;
and 5: synthesis of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -4-aminopiperidine (V)
Heating the compound (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester, sodium ethoxide, 2-methyltetrahydrofuran and water to reflux for 3-4 h;
and after the reaction is finished, carrying out post-treatment to obtain a white solid product.
The method has the advantage that three key intermediates, namely I, II and III are used.
The invention can synthesize the final product under relatively mild conditions. Compared with the prior art, the method has simple process, can obtain the product by only 5 steps of reaction, and needs 6 to 7 steps in the prior art. The method has the advantages of high purity, high yield, short process, easily available and cheap materials, low cost, safe operation and more contribution to industrial production.
The design of the scheme of the process is made because the prior art has the following defects:
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 organic mixed solvent is used in the prior art, so that the organic mixed 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 embody the characteristics of green, environmental protection, low cost and the like well, the technical defects are redesigned through the following scheme, and the specific design process is shown in the embodiment in detail as follows:
1. preparation of intermediate I
The activity of the triflate is utilized, and the yield of the product is better improved.
2. Preparation of intermediate II
4, 5-bis (diphenylphosphino) -9, 9-dimethyl tricyclic dibenzo ligand (Xantphos) is used in the original similar process, but the product purity is poor, the yield is low, BINAP is used as a ligand catalyst, and the yield is increased;
3. preparation of intermediate III
The use of toxic p-toluenesulfonyl chloride or methanesulfonyl chloride is well avoided using the williamson ether synthesis.
4. Preparation of intermediate IV
The expected product can be obtained with high yield by adopting the conventional C-N coupling.
5. Preparation of intermediate V
And removing the protective agent by adopting a conventional deprotection mode under a mild condition to obtain a final product.
It has been found by screening that the above-mentioned drawbacks of the prior art can be overcome with the solution of the invention. The specific screening process is as follows:
1. preparation of intermediate I
Besides trifluoromethanesulfonyl chloride, other trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride or the like is also available, and trifluoromethanesulfonyl chloride is relatively preferable, so that the yield of the product can be effectively improved.
2. Preparation of intermediate II
Except BINAP as ligand catalyst, other ligands 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.
3. Preparation of intermediate III
The use of toxic p-toluenesulfonyl chloride or methanesulfonyl chloride is well avoided using the williamson ether synthesis.
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.
4. Preparation of intermediate IV
The expected product can be obtained with high yield by adopting the conventional C-N coupling. The catalyst and ligand are described in intermediate II.
5. Preparation of intermediate V
And removing the protective agent by adopting a conventional deprotection mode under a mild condition to obtain a final product. Methods for removing the protecting group are many, such as: trifluoroacetic acid, hydrochloric acid and the like, and the scheme in the examples is adopted to well remove BOC in consideration of the fact that the product structure has ether bonds and is unstable.
For specific experimental data see the examples below:
description of the drawings:
FIG. 1, 1H NMR measurement
The specific implementation mode is as follows:
the following examples further illustrate the details of the present invention.
The examples are as follows:
synthesis of 2-chloro-8-triflate quinoline (I)
Adding 50g of compound 2-chloro-8-hydroxyquinoline, 150 g of DMF150ml, 53g of trifluoromethanesulfonyl chloride and 25g of triethylamine into a 250ml three-necked bottle, uniformly stirring, controlling the temperature to be 25-30 ℃ for reaction for 20-30 h, filtering the precipitated solid after the reaction is completed, washing the filter cake with 20ml of n-hexane × 3, drying by blowing at 40 ℃ to obtain 83.39g of white-like solid 2-chloro-8-trifluoromethanesulfonyl benzimidazole, wherein the yield is 95.78%.
Synthesis of tert-butyl 2-chloro-8 (piperidin-4-yl) quinolinecarbamate (II)
Adding 0.2g of BINAP and 70ml of toluene into a 250ml three-necked bottle, stirring for 1h at the temperature of 20-25 ℃, adding 10g of 2-chloro-8-trifluoromethanesulfonic quinoline, 6.41g of tert-butyl piperidin-4-ylcarbamate and 7.8g of potassium carbonate into the bottle, heating the reaction solution to 80-100 ℃ under stirring, keeping the temperature for reaction for 20-30 h.T L C to detect whether the reaction is complete, stopping heating, cooling to 20-30 ℃, adding 50ml of dichloroethane, adding diatomite to filter out solids in the reaction solution, washing a filter cake with 150ml of ethyl acetate, stirring for 8h at 20-25 ℃, filtering out solids precipitated in the solution, washing the filtrate with a 5% disodium hydrogen phosphate solution 2x50ml, concentrating the organic phase to dryness, adding 50ml of acetonitrile, stirring for crystallization for 10-20 h, filtering and drying by air blowing at 40 ℃ to obtain 10.69g of yellow solids, and the yield of 2-chloro-8 (piperidin-4-ylcarbamate) tert-butyl benzoate and 3.92.3.3% of tert-butyl benzoate.
Synthesis of 5- (3-methyloxetane-3-methoxy) benzimidazole (III)
Adding 30.77g of compound 3-methyl-3-oxetanemethanol, THF140ml and 6.95g of metal sodium into a 250ml three-necked flask, heating to 66 ℃ under stirring for refluxing for 4h, cooling to 55 ℃, then adding 40.4g of 5-hydroxybenzimidazole, heating under stirring for refluxing, and reacting for 20-24 h.
Adding 100ml of ethyl acetate into a reaction bottle, stirring for 0.5h at 30-50 ℃ for dissolving, then reducing the temperature to-5 ℃, dropwise adding 30ml of n-hexane, stirring for 1h, performing suction filtration to obtain a light yellow solid, and drying at 40 ℃ to constant weight to obtain 56.41 g, wherein the yield is 85.8%.
Synthesis of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester (IV)
Adding II (50 g), III (30.14 g), potassium carbonate 80g, DIPHOS 4.3g and toluene 700ml into a 2L three-necked bottle, adding palladium acetate 0.9g, uniformly stirring, heating while stirring, controlling the temperature to 80-100 ℃ for reaction for 24-30 h, after the reaction is finished, cooling to 55 ℃, adding dichloroethane 700ml, stirring for 10min, adding diatomite to filter the solid in the reaction solution, washing a filter cake with 500ml of dichloroethane, concentrating the filtrate to dryness, adding ethyl acetate 480ml, heating to reflux, cooling to 20-25 ℃, crystallizing for 10-20 h, filtering the precipitated solid, and drying by blowing at 50 ℃ to obtain a white solid with the yield of 70.51g and 93.90%.
Synthesis of (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -4-aminopiperidine (V)
The compound (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester 5g, sodium ethoxide 2.8g, 2-methyltetrahydrofuran 30ml and water 0.08ml are added to a 100ml three-necked flask, stirred well, the mixture is heated to reflux and stirred under reflux for 3-4 h.
T L C detection, reaction completion, stopping heating, adding 60ml of purified water, extraction layering, extracting a water phase by using ethyl acetate 2 × 20ml, combining organic phases, washing by using saturated sodium chloride solution 20ml, concentrating the organic phase under reduced pressure, adding 30ml of ethyl acetate into the concentrated residue, stirring and crystallizing at 20-25 ℃ for 6h, filtering and precipitating solid, concentrating the filtrate under reduced pressure to dryness, adding 24ml of ethyl acetate into the residue, stirring and crystallizing at 20-25 ℃ for 10-12 h, filtering and precipitating solid, and drying to obtain a white solid product, wherein the yield is 3.68g and 90.3%.
1H NMR measurement (see the attached drawing for details)
(d6-DMSO):9.176(s,1H),8.88-8.91(d,1H,J＝8.7Hz),8.51-8.53(d,1H,J＝9.0Hz)，8.13-8.15(d,1H,J＝9.0Hz)，7.6(d,1H,J＝7.5Hz)，7.49(t,1H,J＝7.9Hz)7.39(d,1H,J＝2.4Hz)，7.29(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),4.14(s,2H),3.74(d,2H,J＝10.1Hz)，2.77(m,3H)，1.91(d,2H,J＝11.1Hz)，1.68(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 (6)
1. A method for producing Crenolanib, comprising the steps of:
step 1: preparation of 2-chloro-8-trifluoromethanesulfonic quinoline
Step 2: preparation of tert-butyl (1- (2-chloroquinolin-8-yl) piperidin-4-yl) carbamate
Step 3, preparation of 5- (3-Methyloxetane-3-methoxy) benzimidazole
Step 4, preparation of 1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester
Step 5, preparation of 1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl } -4-aminopiperidine
2. An intermediate compound which:
3. an intermediate compound which:
4. the method of claim 1, comprising the steps of:
step 1: preparation of 2-chloro-8-trifluoromethanesulfonic quinoline
Reacting 2-chloro-8-hydroxyquinoline with trifluoromethanesulfonyl chloride, filtering and drying to obtain a white solid 2-chloro-8-trifluoromethanesulfonic quinoline;
step 2: preparation of tert-butyl (1- (2-chloroquinolin-8-yl) piperidin-4-yl) carbamate
BINAP, 2-chloro-8-trifluoromethanesulfonic quinoline and tert-butyl piperidin-4-ylcarbamate are mixed and stirred to react, and yellow solid (1- (2-chloroquinolin-8-yl) piperidin-4-yl) carbamic acid tert-butyl ester is obtained after filtration and drying;
and step 3: preparation of 5- (3-methyloxetane-3-methoxy) benzimidazole
3-methyl-3-oxetanyl alcohol and 5-hydroxybenzimidazole react to obtain light yellow solid;
and 4, step 4: preparation of 1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester
Adding palladium acetate into the products obtained in the step 2 and the step 3 for reaction, and filtering and drying to obtain a white solid;
and 5: preparation of 1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -4-aminopiperidine
And 4, carrying out deprotection reaction on the compound obtained in the step 4, filtering and drying to obtain a white solid.
5. The method of claim 1, comprising the steps of:
step 1: synthesis of 2-chloro-8-triflate quinoline (I)
Reacting a compound 2-chloro-8-hydroxyquinoline with trifluoromethanesulfonyl chloride at 25-30 ℃ for 20-30 h, filtering out a precipitated solid after the reaction is completed, and drying to obtain a white-like solid;
step 2: synthesis of tert-butyl (1- (2-chloroquinolin-8-yl) piperidin-4-yl) carbamate (II)
BINAP toluene is evenly stirred, 2-chloro-8-trifluoromethanesulfonic quinoline and piperidine-4-yl tert-butyl carbamate are added, the reaction solution is heated to 80-100 ℃ under stirring, the temperature is kept for reaction for 20-30 h, the reaction is complete, and yellow solid (1- (2-chloroquinoline-8-yl) piperidine-4-yl) tert-butyl carbamate is obtained through aftertreatment;
and step 3: synthesis of 5- (3-methyloxetane-3-methoxy) benzimidazole (III)
Heating and refluxing a compound 3-methyl-3-oxetanyl carbinol and 5-hydroxybenzimidazole for 20-24 hours under stirring, and carrying out aftertreatment to obtain a light yellow solid;
and 4, step 4: synthesis of 1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester (IV)
Adding palladium acetate into the compound II, controlling the temperature to be 80-100 ℃ and reacting for 24-30 h, and after the reaction is finished, carrying out post-treatment to obtain a white solid;
and 5: synthesis of 1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -4-aminopiperidine (V)
Heating a compound (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester, sodium ethoxide, 2-methyltetrahydrofuran and water to reflux for 3-4 h, and carrying out post-treatment after the reaction is finished to obtain a white solid product.
6. The method of claim 1, comprising the steps of:
synthesis of 2-chloro-8-triflate quinoline (I)
Adding 50g of compound 2-chloro-8-hydroxyquinoline, 150 g of DMF150ml, 53g of trifluoromethanesulfonyl chloride and 25g of triethylamine into a 250ml three-necked bottle, uniformly stirring, controlling the temperature to be 25-30 ℃ to react for 20-30 h, filtering the precipitated solid after the reaction is completed, washing the filter cake with 20ml of × 3 of n-hexane, and drying by blowing at 40 ℃ to obtain a white-like solid;
synthesis of tert-butyl (1- (2-chloroquinolin-8-yl) piperidin-4-yl) carbamate (II)
Adding 0.2g of BINAP and 70ml of toluene into a 250ml three-necked bottle, controlling the temperature to be 20-25 ℃, stirring for 1h, adding 10g of 2-chloro-8-trifluoromethanesulfonic benzimidazole, 6.41g of tert-butyl piperidine-4-ylcarbamate and 7.8g of potassium carbonate into the bottle, heating the reaction solution to 80-100 ℃ under stirring, keeping the temperature for reaction for 20-30 h, detecting whether the reaction is complete or not by T L C, stopping heating, cooling to 20-30 ℃, adding 50ml of dichloroethane, adding kieselguhr, filtering solids in the reaction solution, washing a filter cake by using 150ml of ethyl acetate, stirring for 8h at 20-25 ℃, filtering out solids precipitated in the solution, washing the filtrate by using 2x50ml of 5% disodium hydrogen phosphate solution, concentrating the organic phase to be dry again, adding 50ml of acetonitrile, stirring for crystallization at 20-25 ℃ for 10-20 h, filtering the precipitated solids, and drying by blowing at 40 ℃ to obtain yellow solids;
synthesis of 5- (3-methyloxetane-3-methoxy) benzimidazole (III)
Adding 30.77g of compound 3-methyl-3-oxetanemethanol, THF140ml and 6.95g of metal sodium into a 250ml three-necked bottle, heating to 66 ℃ under stirring for refluxing for 4h, cooling to 55 ℃, then adding 40.4g of 5-hydroxybenzimidazole, heating under stirring for refluxing, reacting for 20-24 h, adding 100ml of ethyl acetate into a reaction bottle, stirring at 30-50 ℃ for 0.5h for dissolving, then reducing to-5 ℃, dropwise adding 30ml of n-hexane, stirring for 1h, and performing suction filtration to obtain a light yellow solid;
synthesis of 1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester
II (50 g), III (30.14 g), potassium carbonate 80g, DIPHOS 4.3g and toluene 700ml are added into a 2L three-necked bottle, palladium acetate 0.9g is added, the mixture is stirred uniformly, the temperature is raised under stirring, the temperature is controlled to be 80-100 ℃ for reaction for 24-30 h, after the reaction is finished, the temperature is reduced to 55 ℃, dichloroethane 700ml is added, the mixture is stirred for 10min, kieselguhr is added for filtering solids in the reaction liquid, a filter cake is washed by 500ml of dichloroethane, the filtrate is concentrated to be dry, ethyl acetate 480ml is added, the mixture is heated to reflux, the temperature is reduced to 20-25 ℃, crystallization is carried out for 10-20 h, the precipitated solids are filtered, and air drying is carried out at 50 ℃ to obtain white solids;
synthesis of 1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -4-aminopiperidine
The compound (1- {2- [5- (3-methyl-oxetan-3-ylmethoxy) -benzoimidazol-1-yl ] -quinolin-8-yl } -piperidin-4-yl-carbamic acid tert-butyl ester 5g, sodium ethoxide 2.8g, 2-methyltetrahydrofuran 30ml and water 0.08ml are added to a 100ml three-necked flask, stirred well, the mixture is heated to reflux and stirred under reflux for 3-4 h,
and (3) detecting by T L C, completely reacting, stopping heating, adding 60ml of purified water, extracting and layering, extracting a water phase by using 2 × 20ml of ethyl acetate, combining organic phases, washing by using 20ml of saturated sodium chloride solution, concentrating the organic phase under reduced pressure, adding 30ml of ethyl acetate into the concentrated remainder, stirring and crystallizing at 20-25 ℃ for 6h, filtering and crystallizing precipitated solids, concentrating the filtrate under reduced pressure to dryness, adding 24ml of ethyl acetate into the remainder, stirring and crystallizing at 20-25 ℃ for 10-12 h, filtering and drying the precipitated solids to obtain a white solid product.
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