CN108864050B - Method for synthesizing Arotinib and hydrochloride thereof - Google Patents
Method for synthesizing Arotinib and hydrochloride thereof Download PDFInfo
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- CN108864050B CN108864050B CN201810824114.6A CN201810824114A CN108864050B CN 108864050 B CN108864050 B CN 108864050B CN 201810824114 A CN201810824114 A CN 201810824114A CN 108864050 B CN108864050 B CN 108864050B
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to a method for synthesizing nilotinib and hydrochloride thereof, and particularly relates to the method comprising steps (1) to (3) and step (4) or (5) as described in the specification. The method greatly simplifies the process flow and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to a novel method for synthesizing Arotinib and hydrochloride thereof.
background
the erlotinib is a novel small-molecule multi-target tyrosine kinase inhibitor, can effectively inhibit VEGFR, PDGFR, FGFR, c-Kit and other kinases, and has double effects of resisting tumor angiogenesis and inhibiting tumor growth. The nilotinib is only a single-drug effective oral preparation in the existing anti-angiogenesis targeting drugs for the advanced non-small cell lung cancer, has light adverse reaction and good patient tolerance, and is expected to become a standard drug for three-line treatment of patients with the advanced non-small cell lung cancer. In addition, the nilotinib has a good treatment effect on the non-small cell lung cancer, and also on a plurality of cancer types such as soft tissue sarcoma, ovarian cancer and the like.
The chemical name of the nilotinib is 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine, and the chemical structural formula is as follows:
Currently marketed is the hydrochloride salt of nilotinib,
Patents US2010/0048599 and US2016/030483 of the original research company disclose a synthetic route for the preparation of aritinib hydrochloride and its free base, as follows:
the route is relatively long, the steps are more, and the operation is more complicated. The product of the iron powder reduction step has poor solubility and is difficult to separate from the byproduct iron mud. The cyclopropane segment raw material used in the fifth step has poor stability, which is not beneficial to the quality control and preservation of the raw material. The palladium catalysis step is too close to the API step, which is detrimental to heavy metal residue control in the final product quality. In order to more effectively and simply prepare the erlotinib, a synthetic method of the erlotinib, which is short in process flow, simple to operate and low in cost and is suitable for industrial production, needs to be explored.
Disclosure of Invention
Aiming at the defects and defects in the prior art, the invention aims to provide a synthesis method of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinoline-7-yloxy) methyl) cyclopropylamine hydrochloride (Arotinib hydrochloride), which has the advantages of reasonable process route, simple operation, easily obtained reagents and high yield, and can meet the requirement of industrial scale-up production.
The invention relates to a method for synthesizing 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinoline-7-yloxy) methyl) cyclopropylamine or hydrochloride thereof, which comprises the following steps:
(1) Preparation of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol: carrying out reduction reaction on 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline in an organic solvent under the action of a catalyst to obtain 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) phenoxy) -6-methoxyquinoline-7-ol;
(2) preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol: deprotecting an organic solvent solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol under the action of an acid and self-cyclizing to obtain 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol in one step;
(3) Preparation of tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate: condensing 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-ol and (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl 4-methylbenzenesulfonate in an organic solvent under the action of a catalyst and a base to obtain (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester; and
(4) Preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride: (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester in an organic solvent with hydrogen chloride to deprotect and recrystallize to give 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride; or
(5) preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine: (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester after deprotection in an organic solvent under the action of hydrogen chloride and base liberation gave 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine.
in one embodiment of the present invention, the catalyst in step (1) is palladium on carbon; the using amount of the catalyst is 1-10 wt% of 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline; the hydrogen pressure is 0.1MPa to 1 MPa; and/or the reaction temperature is 40-60 ℃.
In another specific embodiment of the invention, the acid in the step (2) is 1-36% aqueous solution of hydrogen chloride; and/or the reaction temperature is 40-60 ℃.
In another embodiment of the present invention, in the steps (1) and (2), the organic solvent is N-methylpyrrolidone, dimethylformamide or dimethylacetamide.
In another specific embodiment of the present invention, the catalyst in step (3) is potassium iodide or sodium iodide; the using amount of the catalyst is 1-10 wt% of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-ol; the alkali is potassium carbonate, sodium carbonate or potassium tert-butoxide; and/or the reaction temperature is 70-90 ℃.
in another embodiment of the present invention, the organic solvent in step (3) is dimethylformamide.
In another embodiment of the present invention, the reaction temperature in step (4) is 20 to 50 ℃ (preferably room temperature).
In another embodiment of the present invention, the base in step (5) is selected from the group consisting of: sodium carbonate, sodium hydroxide, or a combination thereof.
in another embodiment of the present invention, the organic solvent in steps (4) and (5) is selected from the group consisting of: ethanol, dioxane, ethyl acetate, or a combination thereof.
In another embodiment of the present invention, in the step (4), the recrystallization includes the steps of: concentrating the reaction solution after the protective group is removed, adding ethanol, heating to reflux, cooling to 0-10 ℃, and precipitating 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinoline-7-yloxy) methyl) cyclopropylamine hydrochloride.
The technical scheme provided by the invention has the following technical effects:
1. The reaction steps are few, the original 6-step reaction operation for preparing the Arotinib hydrochloride is reduced to 4-step reaction operation, and the overall yield of the route is high;
2. The reaction operation in each step is simple, only conventional post-treatment or additional purification operation is needed, and an additional column chromatography separation process is not needed;
3. the separation operation of the insoluble intermediate and the iron mud is avoided;
4. Two groups are reduced simultaneously by metal catalytic reaction, so that the reaction efficiency is improved;
5. The raw material cyclopropane derivative used in the route has a stable structure and is easy to obtain.
Therefore, the technical scheme provided by the invention greatly simplifies the process flow and is suitable for industrial production.
Detailed Description
The principles and features of this invention are described below in conjunction with specific embodiments, which are set forth merely to illustrate the invention and are not intended to limit the scope of the invention.
Example synthesis of- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride:
1. preparation of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol:
Placing 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline (52g, 0.1mol) in a 500mL three-necked bottle, adding 280mL of N-methylpyrrolidone, adding wet palladium carbon (5g, 10 wt%), and reacting at 50-55 ℃ under the hydrogen pressure of 0.1-0.2 MPa until the reaction is completely detected by HPLC. The catalyst was removed by filtration, and the mother liquor was distilled under reduced pressure to remove the toluene formed, to give a solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol in N-methylpyrrolidone, which was used directly in the next reaction.
1H NMR(DMSO-d6,400MHz):δ＝10.0(br,1H),8.37(d,J＝5.2Hz,1H),7.50(s, 1H),7.26(s,1H),7.01(t,J＝8.8Hz,1H),6.58(d,J＝8.8Hz,1H),6.26(d,J＝5.2Hz, 1H),5.22(s,2H),3.95(s,3H),3.84(m,4H),2.98(s,2H),1.28(s,3H)ppm
2. preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol:
And (3) putting the obtained N-methylpyrrolidone solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) phenoxy) -6-methoxyquinoline-7-ol into a 500mL three-necked bottle, adding concentrated hydrochloric acid (20g), and reacting at 50-55 ℃ until the reaction is completely detected by HPLC. Water (560mL) was added dropwise at room temperature. Filtering, and washing the filter cake once. Drying gave 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol as a yellowish solid in 23g, purity 98% and overall yield in two steps of 71%.
1H NMR(DMSO-d6,400MHz):δ＝11.42(s,1H),10.11(s,1H),8.35(d,J＝5.2Hz, 1H),7.57(s,1H),7.28(s,1H),7.21(d,J＝8.8Hz,1H),6.98(t,J＝8.0Hz,1H),6.27(s,1H),6.25(d,J＝5.2Hz,1H),3.97(s,3H),2.41(s,3H)ppm
3. Preparation of tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate:
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol (50g, 148mmol) and (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl 4-methylbenzenesulfonate (75.7g, 222mmol) were placed in a 500mL three-necked flask and 300mL of N, N-dimethylformamide was added. Potassium carbonate (40.9g, 296mmol) and potassium iodide (2.45g, 14.8mmol) were added. And (4) reacting at 75-85 ℃ until the reaction is completely detected by HPLC. The reaction mixture was taken up in dichloromethane and washed with saturated brine 6 times. The organic phase was concentrated and the crude product was crystallized from ethanol to give the title compound as a yellow powder 39g with a yield of 52%.
1H NMR(DMSO-d6,400MHz):δ＝11.42(s,1H),8.41(d,J＝5.2Hz,1H),7.59(s, 1H),7.37(s,1H),7.36(s,1H),7.22(d,J＝8.8Hz,1H),6.99(t,J＝8.0Hz,1H),6.32(d, J＝8.8Hz,1H),6.27(s,1H),4.18(s,2H),3.97(s,3H),2.42(s,3H),1.36(s,9H), 0.95-0.70(m,4H)ppm
4. Preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride:
tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate (10g, 19.7mmol) was placed in a 250mL three-necked flask and 50mL of ethanol was added. An ethanol solution of hydrogen chloride (30% wt, 100mL) was added with stirring in an ice water bath. The reaction is completed at room temperature until HPLC detection. And concentrating the reaction solution under reduced pressure to 1-2 volumes, and adding 100mL of ethanol. Heating to reflux temperature, slowly cooling to 0-10 ℃, and filtering to obtain a white solid, namely 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinoline-7-yloxy) methyl) cyclopropylamine dihydrochloride, 7.6g, purity: 99% and yield 80.3%.
1H NMR(DMSO-d6,400MHz):δ＝11.82(s,1H),9.02(s,3H),8.75(d,J＝6.4Hz, 1H),7.84(s,1H),7.83(s,1H),7.30(d,J＝8.4Hz,1H),7.10(t,J＝8.0Hz,1H),6.79(d, J＝6.4Hz,1H),6.31(s,1H),4.44(s,2H),4.08(s,3H),2.43(s,3H),1.3-1.0(m,4H) ppm
example synthesis of- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine:
1. preparation of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol:
Placing 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline (52g, 0.1mol) in a 500mL three-necked bottle, adding 280mL of N, N-dimethylacetamide, adding wet palladium carbon (5g, 10 wt%), and reacting at 50-55 ℃ under the hydrogen pressure of 0.1-0.2 MPa until the reaction is completely detected by HPLC. The catalyst was removed by filtration, and the mother liquor was distilled under reduced pressure to remove the toluene formed, to give a solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol in N, N-dimethylacetamide which was used directly in the next reaction.
2. Preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol:
Putting the obtained N, N-dimethylacetamide ketone solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) phenoxy) -6-methoxyquinoline-7-ol into a 500mL three-necked bottle, adding concentrated hydrochloric acid (20g), and reacting at 50-55 ℃ until the reaction is completely detected by HPLC. Water (560mL) was added dropwise at room temperature. Filtering, and washing the filter cake once. Drying gave 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol as a yellowish solid in 23g, purity 98% and overall yield in two steps of 71%.
3. Preparation of tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate:
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol (50g, 148mmol) is placed in a 500mL three-necked flask and 300mL of N, N-dimethylformamide is added. Potassium carbonate (40.9g, 296mmol) and potassium iodide (2.22g, 14.8mmol) were added. (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl 4-methylbenzenesulfonate (75.7g, 222mmol) was added in portions at 75-85 ℃. Stirring was continued until the reaction was complete as detected by HPLC. The reaction mixture was taken up in dichloromethane and washed with saturated brine 6 times. The organic phase was concentrated and the crude product was crystallized from ethanol to yield the title compound as a yellow powder 42g with a yield of 56%.
4. preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine:
Tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate (10g, 19.7mmol) was placed in a 250mL three-necked flask and 50mL of ethanol was added. An ethanol solution of hydrogen chloride (30% wt, 100mL) was added with stirring in an ice water bath. The reaction is completed at room temperature until HPLC detection. Concentrating the reaction solution under reduced pressure to 1-2 volumes, adding the reaction solution into dichloromethane, washing with saturated sodium carbonate, concentrating an organic phase, and pulping the concentrate with n-heptane to obtain 7.2g of a light yellow solid, namely 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine, wherein the purity is as follows: 99% and yield 90%.
1H NMR(DMSO-d6,400MHz):δ＝11.50(s,1H),8.42(d,J＝5.2Hz,1H),7.61(s, 1H),7.38(s,1H),7.22(d,J＝8.8Hz,1H),6.99(t,J＝8.0Hz,1H),6.33(d,J＝5.2Hz, 1H),6.27(s,1H),4.12(s,2H),3.99(s,3H),2.42(s,3H),0.85-0.65(m,4H)ppm
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (15)
1. a method for synthesizing 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine or its hydrochloride salt, comprising the steps of:
(1) Preparation of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol: carrying out reduction reaction on 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline in an organic solvent under the action of a catalyst to obtain an organic solvent solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) phenoxy) -6-methoxyquinoline-7-ol; the catalyst is palladium carbon;
(2) Preparing 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol, i.e. an organic solvent solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol is deprotected under the action of an acid and is subjected to a one-step self-cyclization reaction to obtain 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol, wherein the acid is a 1 3536% aqueous hydrogen chloride solution;
(3) Preparation of tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate: condensing 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-ol and (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl 4-methylbenzenesulfonate in an organic solvent under the action of a catalyst and a base to obtain (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester; and
(4) Preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride: (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester in an organic solvent with hydrogen chloride to deprotect and recrystallize to give 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride; or
(5) preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine: (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester after deprotection in an organic solvent under the action of hydrogen chloride and base liberation gave 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine.
2. The method of claim 1, wherein in step (1), the catalyst is used in an amount of 1 ~ 10wt% of 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline.
3. The synthesis method according to claim 1, wherein in the step (1), the pressure of hydrogen used in the reduction reaction is 0.1MPa ~ 1 MPa.
4. the synthesis method according to claim 1, wherein in the step (1), the reaction temperature is 40 ~ 60 ℃.
5. the method according to claim 1, wherein in the step (2), the reaction temperature is 40 ~ 60 degrees.
6. the method according to claim 1, wherein in the steps (1) and (2), the organic solvent is N-methylpyrrolidone, dimethylformamide or dimethylacetamide.
7. The synthesis method according to claim 1, wherein in the step (3), the catalyst is potassium iodide or sodium iodide.
8. the process of claim 1, wherein in step (3), the catalyst is used in an amount of 1 ~ 10wt% of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol.
9. The method according to claim 1, wherein in the step (3), the base is potassium carbonate, sodium carbonate or potassium tert-butoxide.
10. The method of claim 1, wherein in step (3), the reaction temperature is 70 ~ 90 degrees.
11. the method according to claim 1, wherein in the step (3), the organic solvent is dimethylformamide.
12. The method according to claim 1, wherein in the step (4), the reaction temperature is 20 ~ 50 ℃.
13. The method of claim 1, wherein in step (5), the base is selected from the group consisting of: sodium carbonate, sodium hydroxide, or a combination thereof.
14. The method according to claim 1, wherein in the steps (4) and (5), the organic solvent is selected from the group consisting of: ethanol, dioxane, ethyl acetate, or a combination thereof.
15. The synthesis method according to claim 1, wherein in the step (4), the recrystallization comprises the steps of concentrating the reaction solution from which the protective group is removed, adding ethanol, heating to reflux, and cooling to 0 ~ 10oand C, 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride is precipitated.
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| CN111630045A (en) * | 2018-02-11 | 2020-09-04 | 正大天晴药业集团股份有限公司 | Crystal of quinoline derivative |
| CN110357856B (en) * | 2018-04-09 | 2021-02-26 | 新发药业有限公司 | Arotinib hydrochloride intermediate and preparation method of Arotinib hydrochloride |
| WO2020020190A1 (en) * | 2018-07-24 | 2020-01-30 | 正大天晴药业集团股份有限公司 | Method for synthesizing quinoline derivative |
| CN110376296A (en) * | 2019-06-06 | 2019-10-25 | 张云 | Pacify the quantitative detecting method that sieve replaces Buddhist nun's medicament residue in blood |
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