CN115215788B - Preparation method of ceritinib key intermediate - Google Patents
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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Abstract
The invention relates to a preparation method of a ceritinib key intermediate, which is characterized in that the method is used for finally preparing the ceritinib key intermediate N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine through five steps of reduction reaction, bromination reaction, acetylation reaction, grignard reaction and hydrolysis reaction in sequence.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of a ceritinib key intermediate.
Background
Ceritinib (Ceritinib), a trade name Zykadia, an Anaplastic Lymphoma Kinase (ALK) inhibitor developed by nova (Novartis) corporation, can block oncogenic proteins, is suitable for the treatment of non-small cell lung cancer (NSCLC) patients with ALK positive metastasis intolerant to Crizotinib (Crizotinib), is approved by the us FDA for the 29 th month 2014, and is then approved by the European Medical Administration (EMA), the japanese drug and medical equipment administration (PMDA) for the 2014, and 2016, respectively. 7 months 2017, ceritinib was approved by the european union as a first-line treatment of ALK-positive non-small cell lung cancer drug with broad application and market prospects. The structural formula of ceritinib is shown as follows:
the key intermediate N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine is used in the synthesis route of the prior reported ceritinib, and has the following structural formula:
the synthesis methods reported at present and related to the key intermediates are all required to be subjected to a palladium catalytic coupling step and a palladium-carbon high-pressure hydrogenation step, and the method is also a key bottleneck with great difficulty and high cost in the industrial production of the intermediate products.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides the preparation method of the ceritinib key intermediate, which has the advantages of easily available raw materials, low cost, mild reaction conditions and easy control, and is more suitable for large-scale industrial production.
The technical scheme adopted by the invention is as follows:
a preparation method of a ceritinib key intermediate comprises the following steps:
step (1): the compound of formula 1 is reduced to produce a compound of formula 2;
step (2): bromination of the compound of formula 2 to produce a compound of formula 3;
step (3): the compound of formula 3 is subjected to acetylation reaction to generate a compound of formula 4;
step (4): the compound of formula 4 is subjected to Grignard reaction to generate a compound of formula 5;
step (5): the compound of the formula 5 is subjected to hydrolysis reaction to generate a compound of the formula 6, namely the key intermediate N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine of the ceritinib.
The reducing agent used in the reduction reaction in the step (1) is one or more of ferric trichloride, tin dichloride and sodium hydrosulfite.
The specific operation of the reduction reaction in step (1) is as follows:
dissolving a compound of formula 1 in methanol, sequentially adding active carbon, ferric trichloride and hydrazine hydrate, carrying out reflux reaction, filtering and concentrating the reacted system, adding dichloromethane, washing with water, and saturating NaHCO 3 Washing, drying and concentrating to obtain the compound of the formula 2.
The brominating agent used in the brominating reaction in the step (2) is one or more of NBS, liquid bromine and dibromohydantoin.
The bromination reaction in step (2) is specifically performed as follows:
dissolving the compound of the formula 2 in dichloromethane, cooling to-10 ℃, slowly adding NBS until the addition is finished, continuing the reaction for 3 hours, and after the reaction is finished, washing with 5% sodium thiosulfate solution, washing with water, washing with saturated sodium chloride, drying, concentrating and crystallizing to obtain the compound of the formula 3.
The acetylating reagent used in the acetylating reaction in the step (3) is one or two of acetyl chloride and acetic anhydride.
The specific operation of the acetylation reaction in step (3) is as follows:
dissolving a compound of formula 3 in dichloromethane, adding triethylamine, cooling to 0 ℃, dropwise adding acetic anhydride, stirring at room temperature for 12 hours until the reaction is finished, and sequentially carrying out hydrochloric acid washing and saturated NaHCO 3 Washing with saturated sodium chloride, drying, and concentrating to obtain compound of formula 4.
The Grignard reagent used in the Grignard reaction in the step (4) is one or more of isopropyl Grignard reagent, methyl Grignard reagent and ethyl Grignard reagent.
The specific operation of the grignard reaction in step (4) is as follows:
dissolving a compound of formula 4 in anhydrous THF, dropwise adding an isopropyl Grignard reagent at-10 ℃, and keeping the temperature for 3 hours for later use; dissolving 1-tert-Butoxycarbonyl-4-iodopiperidine in anhydrous THF, adding anhydrous CoCl 2 . And (3) cooling the reaction solution to 10 ℃, and then dropwise adding the prepared Grignard reagent. After the completion of the dropwise addition, the reaction mixture was reacted at room temperature for 12 hours. Washing the reaction solution by saturated ammonium chloride, drying, concentrating to obtain a crude product, and recrystallizing the crude product by methanol to obtain a compound of the formula 5;
the hydrolysis reagent used in the hydrolysis reaction in the step (5) is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
The hydrolysis reaction in the step (5) is specifically performed as follows:
dissolving a compound of formula 5 in ethanol, adding a NaOH solution, reacting for 12 hours at 70 ℃, cooling to 0 ℃ after the reaction is completed, adjusting the pH of a system to 7-8 by hydrochloric acid, concentrating to remove ethanol, filtering, washing a filter cake by water and isopropanol, and drying to obtain the compound of formula 6.
The beneficial effects of the invention are as follows:
according to the preparation method of the ceritinib key intermediate, the N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine serving as the ceritinib key intermediate is finally prepared through five steps of reduction reaction, bromination reaction, acetylation reaction, grignard reaction and hydrolysis reaction in sequence.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, based on the examples herein, which are within the scope of the invention as defined by the claims, will be within the scope of the invention as defined by the claims.
Example 1
The embodiment provides a preparation method of a ceritinib key intermediate, which comprises the following steps:
step (1): firstly, carrying out nitration and alkylation self-preparation according to the methods of documents CN110590557 and WO2016199020 by taking p-methylphenol as a raw material to obtain a compound (CAS No. 78944-97-5) of a formula 1;
dissolving 1.95kg of compound of formula 1 in 16L of methanol, adding 1kg of activated carbon, adding 1kg of ferric trichloride, adding 600ml of 80% hydrazine hydrate, refluxing for 16 hours, analyzing, filtering, concentrating, adding 16L of dichloromethane, washing with water, and adding NaHCO 3 Washing with saturated solution, drying and concentrating to obtain 1.55kg of crude compound of formula 2 with purity of 85% and yield of 79.8%; directly used for the next step; LCMS (ESI) m/z=166.1 [ m+h ] for compounds of formula 2 as detected] + ；
Step (2): 1.55kg of the compound of the formula 2 is dissolved in 15L of dichloromethane, the temperature is reduced to minus 10 ℃, NBS1.6 kg is slowly added, the addition is completed for 2 hours, the temperature is kept for 3 hours, 10L of sodium thiosulfate 5% solution is added for washing, water washing and saturated sodium chloride washing are carried out, 2.4kg of a crude product of the compound of the formula 3 is obtained after drying and concentration, 1.6kg of a pure product is obtained after crystallization by 6L of n-hexane, the purity is 97%, and the yield is 81.6%;
the results of the test for the compound of formula 3 are as follows:
LCMS(ESI)m/z＝244.0[M+H] + ；
1H NMR(400MHz,CDCl3):δ＝9.0(s,2H),7.18(s,1H),6.92(s,1H),4.37(m, 1H),2.30(s,3H),1.25(d,J＝6.1Hz,6H)；
step (3): dissolving 1.6kg of a compound of formula 3 in 16L of dichloromethane, adding 1kg of triethylamine, cooling to 0 ℃, dropwise adding 1kg of acetic anhydride, stirring at room temperature for 12 hours, analyzing, finishing the reaction, washing with 1N hydrochloric acid, washing with saturated sodium bicarbonate and saturated salt, drying, concentrating to obtain 1.69kg of a compound of formula 4, wherein the purity is 95%, and the yield is 90.2%; LCMS (ESI) m/z=286.0 [ m+h ] for compounds of formula 4, as detected] + ；
Step (4): 1.6kg of the compound of formula 4 was dissolved in 16L of anhydrous THF, and 7L of isopropyl magnesium chloride was added dropwise at-10℃and this temperature was maintained for 3 hours for use. 2.3kg of 1-tert-butoxycarbonyl-4-iodopiperidine were dissolved in 9L of anhydrous THF and 180g of anhydrous CoCl were added 2 . And (3) cooling the reaction solution to 10 ℃, and then dropwise adding the prepared Grignard reagent. After the completion of the dropwise addition, the reaction mixture was reacted at room temperature for 12 hours. Washing the reaction solution with saturated ammonium chloride, drying, concentrating to obtain a crude product, recrystallizing the crude product with methanol to obtain 1.44kg of the compound of formula 5, wherein the purity is 95%, and the yield is 66.1%;
the results of the test for the compound of formula 5 are as follows:
LCMS(ESI)m/z＝391.3[M+H] + ；
1H NMR(400MHz,CDCl3):δ＝9.0(s,1H),6.43(s,1H),6.36(s,1H),4.43(m, 1H),3.49(br,s,2H),2.62-2.72(m,3H),2.14(s,3H),2.05(s,3H),1.57-1.60(m,2H),1.37-1.44(m,2H),1.32(s,9H),1.15(d,J＝6.1Hz,6H)；
step (5): 1.4kg of the compound of formula 5 is dissolved in 14L of ethanol, and 2.6L of 6N NaOH solution is added; the reaction liquid reacts for 12 hours at 70 ℃, and the detection reaction is complete; the reaction solution was cooled to 0℃and then the pH of the reaction system was adjusted to 7-8 with 1N hydrochloric acid, followed by concentration to remove ethanol. The mixture after concentration was filtered, and the filter cake was washed with water, isopropanol and dried to give 1.14kg of the compound of formula 6 with a purity of 97% and a yield of 91.5%.
The results of the detection of the final product are as follows:
LCMS(ESI)m/z＝349.2[M+H] + ；
1H NMR(400MHz,CDCl3):δ＝9.1(s,2H),6.53(s,1H),6.46(s,1H),4.53(m, 1H),3.59(br,s,2H),2.72-2.82(m,3H),2.24(s,3H),1.67-1.70(m,2H),1.47-1.54(m,2H),1.42(s,9H),1.25(d,J＝6.1Hz,6H)；
the obtained compound of formula 6 is proved to be a key intermediate N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine of ceritinib.
Example 2
The present embodiment provides another preparation method of a key intermediate of ceritinib, the reaction flow is referred to in embodiment 1, and the method in the embodiment includes the following steps:
step (1): 195.22g of the compound of formula 1 is dissolved in 2L of methanol, 120g of activated carbon is added, 189.62g of tin dichloride is added, 60ml of 80% hydrazine hydrate is added, reflux is carried out for 18 hours, analysis is carried out, the reaction is finished, filtration and concentration are carried out, dichloromethane 2L is added, water washing and NaHCO are carried out 3 Washing with saturated solution, drying and concentrating to obtain 97.9g of crude compound of formula 2 with purity of 81% and yield of 48.0%; directly used for the next step; LCMS (ESI) m/z=166.1 [ m+h ] for compounds of formula 2 as detected] + ；
Step (2): 97.9g of compound of formula 2 is dissolved in 1L of dichloromethane, the temperature is reduced to minus 10 ℃, 210.84g of bromine is slowly dripped into the solution, the solution is dripped into the solution for 1 hour, the temperature is kept for 4 hours, the reaction is detected to be finished, 1L of sodium thiosulfate 5% solution is added for washing, water washing and saturated salt water washing are carried out, 140.23g of crude compound of formula 3 is obtained after drying and concentration, 87.5g of pure product is obtained after crystallization of the crude compound with 6L of normal hexane, the purity is 95.5%, and the yield is 74.7%. LCMS (ESI) m/z=244.0 [ m+h ] for compounds of formula 3 as detected] + ；
Step (3): dissolving 87.5g of a compound of formula 3 in 1L of dichloromethane, adding 54.7g of triethylamine, cooling to 0 ℃, dropwise adding 58.5g of acetic anhydride, stirring at room temperature for 12 hours, analyzing, finishing the reaction, washing with 1N hydrochloric acid, washing with saturated sodium bicarbonate and saturated salt water, drying, concentrating to obtain 97.2g of a compound of formula 4, wherein the purity is 93%, and the yield is 94.8%; LCMS (ESI) m/z=286.0 [ m ] for compounds of formula 4, as detected+H] + ；
Step (4): 97.2g of the compound of formula 4 are dissolved in 1L of anhydrous THF, 50ml of isopropyl magnesium chloride are added dropwise at-10℃and this temperature is maintained for 3 hours for further use. 168.2g of 1-tert-butoxycarbonyl-4-iodopiperidine were dissolved in 800ml of anhydrous THF and 16g of anhydrous CoCl were added 2 . And (3) cooling the reaction solution to 10 ℃, and then dropwise adding the prepared Grignard reagent. After the completion of the dropwise addition, the reaction mixture was reacted at room temperature for 12 hours. Washing the reaction solution by saturated ammonium chloride, drying, concentrating to obtain a crude product, and recrystallizing the crude product by methanol to obtain 105.3g of the compound of the formula 5, wherein the purity is 95%, and the yield is 79.4%;
the results of the test for the compound of formula 5 are as follows:
LCMS(ESI)m/z＝391.3[M+H] + ；
1H NMR(400MHz,CDCl3):δ＝9.0(s,1H),6.43(s,1H),6.36(s,1H),4.43(m, 1H),3.49(br,s,2H),2.62-2.72(m,3H),2.14(s,3H),2.05(s,3H),1.57-1.60(m,2H),1.37-1.44(m,2H),1.32(s,9H),1.15(d,J＝6.1Hz,6H)；
step (5): 105.3g of the compound of formula 5 are dissolved in 1L of ethanol, and 210ml of 6N KOH solution are added; the reaction liquid reacts for 12 hours at 70 ℃, and the detection reaction is complete; the reaction solution was cooled to 0℃and then the pH of the reaction system was adjusted to 7-8 with 1N hydrochloric acid, followed by concentration to remove ethanol. The concentrated mixture was filtered, and the filter cake was washed with water, isopropanol and dried to give 80.8g of the compound of formula 6 in 96% purity with a yield of 86.0%.
The results of the detection of the final product are as follows:
LCMS(ESI)m/z＝349.2[M+H] + ；
1H NMR(400MHz,CDCl3):δ＝9.1(s,2H),6.53(s,1H),6.46(s,1H),4.53(m, 1H),3.59(br,s,2H),2.72-2.82(m,3H),2.24(s,3H),1.67-1.70(m,2H),1.47-1.54 (m,2H),1.42(s,9H),1.25(d,J＝6.1Hz,6H)；
the obtained compound of formula 6 is proved to be a key intermediate N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine of ceritinib.
Example 3
The present embodiment provides another preparation method of a key intermediate of ceritinib, the reaction flow is referred to in embodiment 1, and the method in the embodiment includes the following steps:
step (1): dissolving 19.52g of the compound of formula 1 in 200ml of methanol, adding 12.00g of activated carbon, adding 17.41g of sodium hydrosulfite, adding 6ml of 80% hydrazine hydrate, refluxing for 18 hours, analyzing, filtering, concentrating, adding 200ml of dichloromethane, washing with water, and adding NaHCO 3 Washing with saturated solution, drying and concentrating to obtain 7.49g of crude compound of formula 2 with purity of 84% and yield of 38.1%; directly used for the next step; LCMS (ESI) m/z=166.1 [ m+h ] for compounds of formula 2 as detected] + ；
Step (2): 7.49g of the compound of formula 2 is dissolved in 10ml of dichloromethane, cooled to-10 ℃, 13.00g of dibromohydantoin is slowly added and dropwise added for 0.5 hour, the temperature is kept for 4 hours, the detection reaction is finished, 200ml of sodium thiosulfate 5% solution is added for washing, water washing, saturated salt water washing, drying and concentration are carried out to obtain 10.5g of crude compound of formula 3, 500ml of normal hexane is used for crystallizing the crude product, and the pure product of 5.2g, the purity of 97% and the yield of 55.6% are obtained. LCMS (ESI) m/z=244.0 [ m+h ] for compounds of formula 2 as detected] + ；
Step (3): dissolving 5.2g of a compound of formula 3 in 50ml of dichloromethane, adding 4.3g of triethylamine, cooling to 0 ℃, dropwise adding 2.5g of acetyl chloride, stirring at room temperature for 12 hours, analyzing, finishing the reaction, washing with 1N hydrochloric acid, washing with saturated sodium bicarbonate and saturated salt water, drying, concentrating to obtain 5.1g of the compound of formula 4, wherein the purity is 95%, and the yield is 83.5%; LCMS (ESI) m/z=286.0 [ m+h ] for compounds of formula 4, as detected] + ；
Step (4): 5.1g of the compound of formula 4 are dissolved in 50ml of anhydrous THF and 10ml of isopropyl magnesium chloride are added dropwise at-10℃and this temperature is maintained for 3 hours for further use. 6.6g of 1-tert-butoxycarbonyl-4-iodopiperidine were dissolved in 10ml of anhydrous THF, and 0.8g of anhydrous CoCl was added 2 . And (3) cooling the reaction solution to 10 ℃, and then dropwise adding the prepared Grignard reagent. After the completion of the dropwise addition, the reaction mixture was reacted at room temperature for 12 hours. Washing the reaction solution by saturated ammonium chloride, drying, concentrating to obtain a crude product, and recrystallizing the crude product by methanol to obtain 4.3g of a compound of formula 5, wherein the purity is 94.7%, and the yield is 62.3%;
the results of the test for the compound of formula 5 are as follows:
LCMS(ESI)m/z＝391.3[M+H] + ；
1H NMR(400MHz,CDCl3):δ＝9.0(s,1H),6.43(s,1H),6.36(s,1H),4.43(m, 1H),3.49(br,s,2H),2.62-2.72(m,3H),2.14(s,3H),2.05(s,3H),1.57-1.60(m,2H),1.37-1.44(m,2H),1.32(s,9H),1.15(d,J＝6.1Hz,6H)；
step (5): 4.3g of the compound of formula 5 are dissolved in 15ml of ethanol, 8ml of a 6N LiOH solution are added; the reaction liquid reacts for 12 hours at 70 ℃, and the detection reaction is complete; the reaction solution was cooled to 0℃and then the pH of the reaction system was adjusted to 7-8 with 1N hydrochloric acid, followed by concentration to remove ethanol. The mixture after concentration was filtered, and the filter cake was washed with water, isopropanol and dried to give 2.8g of the compound of formula 6, 97% purity, 72.3% yield. Namely the key intermediate N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine of the ceritinib.
The results of the detection of the final product are as follows:
LCMS(ESI)m/z＝349.2[M+H] + ；
1H NMR(400MHz,CDCl3):δ＝9.1(s,2H),6.53(s,1H),6.46(s,1H),4.53(m, 1H),3.59(br,s,2H),2.72-2.82(m,3H),2.24(s,3H),1.67-1.70(m,2H),1.47-1.54(m,2H),1.42(s,9H),1.25(d,J＝6.1Hz,6H)；
the obtained compound of formula 6 is proved to be a key intermediate N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine of ceritinib.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. The preparation method of the ceritinib key intermediate is characterized by comprising the following steps of:
；
step (1): the compound of formula 1 is reduced to produce a compound of formula 2;
step (2): bromination of the compound of formula 2 to produce a compound of formula 3;
step (3): the compound of formula 3 is subjected to acetylation reaction to generate a compound of formula 4;
step (4): the compound of formula 4 is subjected to Grignard reaction to generate a compound of formula 5;
step (5): the compound of the formula 5 is subjected to hydrolysis reaction to generate a compound of the formula 6, namely the key intermediate N-Boc-4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine of the ceritinib.
2. The preparation method of the ceritinib key intermediate according to claim 1, wherein the reducing agent used in the reduction reaction in the step (1) is one or more of ferric chloride, stannous chloride and sodium hydrosulfite.
3. The method for preparing a ceritinib key intermediate according to claim 2, wherein the specific operation of the reduction reaction in step (1) is as follows:
dissolving a compound of formula 1 in methanol, sequentially adding active carbon, ferric trichloride and hydrazine hydrate, carrying out reflux reaction, filtering and concentrating the reacted system, adding dichloromethane, washing with water, and saturating NaHCO 3 Washing, drying and concentrating to obtain the compound of the formula 2.
4. The preparation method of the ceritinib key intermediate according to claim 1, wherein the brominating agent used in the bromination reaction in the step (2) is one or more of NBS, liquid bromine and dibromohydantoin.
5. The method for preparing a ceritinib key intermediate according to claim 4, wherein the bromination reaction in step (2) is specifically performed as follows:
dissolving the compound of the formula 2 in dichloromethane, cooling to-10 ℃, slowly adding NBS until the addition is finished, continuing the reaction for 3 hours, and after the reaction is finished, washing with 5% sodium thiosulfate solution, washing with water, washing with saturated sodium chloride, drying, concentrating and crystallizing to obtain the compound of the formula 3.
6. The method for preparing a ceritinib key intermediate according to claim 1, wherein the acetylating reagent used in the acetylating reaction in the step (3) is one or two of acetyl chloride and acetic anhydride.
7. The method for preparing a ceritinib key intermediate according to claim 6, wherein the specific operation of the acetylation reaction in step (3) is as follows:
dissolving a compound of formula 3 in dichloromethane, adding triethylamine, cooling to 0 ℃, dropwise adding acetic anhydride, stirring at room temperature for 12 hours until the reaction is finished, and sequentially carrying out hydrochloric acid washing and saturated NaHCO 3 Washing with saturated sodium chloride, drying, and concentrating to obtain compound of formula 4.
8. The preparation method of the ceritinib key intermediate according to claim 1, wherein the grignard reagent used in the grignard reaction in the step (4) is one or more of isopropyl grignard reagent, methyl grignard reagent and ethyl grignard reagent;
the hydrolysis reagent used in the hydrolysis reaction in the step (5) is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
9. The method for preparing a ceritinib key intermediate according to claim 8, wherein the grignard reaction in step (4) is specifically performed as follows:
dissolving a compound of formula 4 in anhydrous THF, dropwise adding an isopropyl Grignard reagent at-10 ℃, and keeping the temperature for 3 hours for later use; dissolving 1-tert-Butoxycarbonyl-4-iodopiperidine in anhydrous THF, adding anhydrous CoCl 2 The method comprises the steps of carrying out a first treatment on the surface of the Dropping the prepared Grignard reagent after the reaction solution is cooled to 10 ℃; after the dripping is finished, the reaction solution reacts for 12 hours at room temperature; washing the reaction solution by saturated ammonium chloride, drying, concentrating to obtain a crude product, and recrystallizing the crude product by methanol to obtain the compound of the formula 5.
10. The method for preparing a ceritinib key intermediate according to claim 8, wherein the hydrolysis reaction in step (5) is specifically performed as follows:
dissolving a compound of formula 5 in ethanol, adding a NaOH solution, reacting for 12 hours at 70 ℃, cooling to 0 ℃ after the reaction is completed, adjusting the pH of a system to 7-8 by hydrochloric acid, concentrating to remove ethanol, filtering, washing a filter cake by water and isopropanol, and drying to obtain the compound of formula 6.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8901304B1 (en) * | 2013-11-05 | 2014-12-02 | King Fahd University Of Petroleum And Minerals | Benzo[D]imidazole derivatives of piperidine and piperazine |
| CN104356050A (en) * | 2014-09-30 | 2015-02-18 | 常州市勇毅生物药业有限公司 | Preparation method of ceritinib |
| WO2016199020A1 (en) * | 2015-06-08 | 2016-12-15 | Dr. Reddy's Laboratories Limited | Process for preparation of ceritinib |
| CN106565593A (en) * | 2015-10-10 | 2017-04-19 | 常州市勇毅生物药业有限公司 | A ceritinib preparing method |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8901304B1 (en) * | 2013-11-05 | 2014-12-02 | King Fahd University Of Petroleum And Minerals | Benzo[D]imidazole derivatives of piperidine and piperazine |
| CN104356050A (en) * | 2014-09-30 | 2015-02-18 | 常州市勇毅生物药业有限公司 | Preparation method of ceritinib |
| WO2016199020A1 (en) * | 2015-06-08 | 2016-12-15 | Dr. Reddy's Laboratories Limited | Process for preparation of ceritinib |
| CN106565593A (en) * | 2015-10-10 | 2017-04-19 | 常州市勇毅生物药业有限公司 | A ceritinib preparing method |
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