CN110143947A - A kind of preparation method of Ceritinib analog - Google Patents

A kind of preparation method of Ceritinib analog Download PDF

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CN110143947A
CN110143947A CN201910454738.8A CN201910454738A CN110143947A CN 110143947 A CN110143947 A CN 110143947A CN 201910454738 A CN201910454738 A CN 201910454738A CN 110143947 A CN110143947 A CN 110143947A
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reaction
compound
methyl
phenyl
tetrahydropyridine
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CN110143947B (en
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吴文萱
李晓林
罗宇
占莉
康立涛
李倩
杨世琼
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SHANGHAI BIOCOMPOUNDS CHEMLAB CO Ltd
East China Normal University
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SHANGHAI BIOCOMPOUNDS CHEMLAB CO Ltd
East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D401/12—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

Abstract

The invention discloses a kind of chloro- N of Ceritinib analog 5-2(2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl)-N4(2- (isopropelsulfonyl) phenyl) pyrimidine -2; the preparation method of 4- diamine dihydrochloride; this method is with 1- benzyl -4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -1; 2; 3; 6- tetrahydropyridine is starting material, and nucleophilic substitution occurs with trichloroethyl chloroformate and generates chemical compounds I；Then nitro is reduced into amino under reducing agent effect by chemical compounds I, generates compound ii；It is deprotected under reducing agent effect again, obtains compound III；The hydrochloride and compounds Ⅳ of final compound III carry out nucleophilic substitution, generate the chloro- N of compound V, that is, 5-2(2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl)-N4(2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride.Synthetic route of the invention is short, easy to operate, safety is good, product yield is high, quality is high, synthesis cost is low.

Description

A kind of preparation method of Ceritinib analog
Technical field
The present invention relates to technical field of compound preparation, and in particular to the Ceritinib analog, that is, chloro- N of 5-2(2- isobutyl Base -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl)-N4(2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- two The preparation method of amine dihydrochloride.
Background technique
Ceritinib (Ceritinib) is selective ALK kinase inhibitor, is applicable in there is anaplastic lymphoma kinase (ALK)-positive shift replaces Buddhist nun's progress or the treatment of intolerable non-small cell lung cancer (NSCLC) patient to gram azoles.Currently, During synthesizing Ceritinib dihydrochloride (as shown in levoform), inevitably following impurity, i.e. Ceritinib Analog compounds V (as shown in right formula):
Therefore in the synthesis and quality inspection of Ceritinib, artificial synthesized Ceritinib analog, that is, compound V out It can be used as standard preparation, compared with institute's band impurity in Ceritinib product, have ten to the quality testing of Ceritinib drug Divide important meaning, but at present about the chloro- N of compound V5-2(2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- Base) phenyl)-N4The synthetic method of (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride rarely has document report Road.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of preparation methods of Ceritinib analog, with 1- benzyl- 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -1,2,3,6- tetrahydropyridines are raw material, first and trichloroethyl chloroformate Nucleophilic substitution occurs, obtains intermediate (I), is then walked using reduction reaction, deprotection reaction, nucleophilic substitution etc. Suddenly, the chloro- N of 5- is prepared2(2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl)-N4(2- (isopropyl sulphur Acyl group) phenyl) pyrimidine -2,4- diamine dihydrochloride.This method has that synthetic route is short, easy to operate, safety is good, product yield Advantage high, quality is high, synthesis cost is low, easy to industrialized production.
To achieve the goals above, the technical solution adopted by the present invention is that:
A kind of preparation method of Ceritinib analog, this method comprising the following specific steps
Step 1: 1- benzyl -4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -1,2,3,6- tetrahydropyridine is added In first reaction dissolvent, nucleophilic substitution occurs with trichloroethyl chloroformate, obtains 2,2,2- trichloroethyl 4- (5- isopropyl oxygen Base -2- methyl -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester, that is, compound I；Wherein, 1- benzyl -4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) the ratio between -1,2,3,6- tetrahydropyridine and the mole of trichloroethyl chloroformate be 1: 1.0~1.5, reaction temperature is 10~50 DEG C, and the time of reaction is 1~4 hour；
Step 2: compound I made from step 1 is dissolved in the second reaction dissolvent and ferric trichloride, active carbon, hydrazine hydrate Reaction, obtains 2,2,2- trichloroethyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- dihydropyridine -1 (2H)-carboxylic Tert-butyl acrylate, that is, compound II；Wherein, the ratio between mole of the compound I and ferric trichloride, active carbon, hydrazine hydrate is 1: 0.1~0.5: 2~10: 5~20；Reaction temperature is 50~80 DEG C；The time of reaction is 4~15 hours；
Step 3: compound II made from step 2 being added in third reaction dissolvent, reducing agent is added and be deprotected instead It answers, obtains 2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline dihydrochloride, that is, compound III；Its In, the ratio between mole of the compound II and reducing agent is 1: 10~35, and reaction temperature is 10~50 DEG C, and the time of reaction is 2~8 hours；
Step 4: by compound III made from step 3 and the chloro- N- of 2,5- bis- (2- (isopropelsulfonyl) phenyl) pyrimidine- 4- amine, that is, compounds Ⅳ is dissolved in the 4th reaction dissolvent, generates the chloro- N of the Ceritinib analog 5- by nucleophilic substitution2- (2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl)-N4(2- (isopropelsulfonyl) phenyl) is phonetic Pyridine -2,4- diamine dihydrochloride, that is, compound V；Wherein, the ratio between mole of the compound III and compounds Ⅳ is 1: 1.0 ~1.5, reaction temperature is 75~110 DEG C, and the time of reaction is 6~20 hours；Specific synthesis process is shown below:
In the step 1, the first reaction dissolvent is n,N-Dimethylformamide, tetrahydrofuran or acetonitrile；It is described to have reacted Cheng Hou further include: solvent evaporated carries out column chromatographic purifying with ethyl acetate and petroleum ether volume ratio for 1: 8.
In the step 2, the second reaction dissolvent is dehydrated alcohol, anhydrous methanol or tetrahydrofuran；It is described after the reaction was completed Further include: it filtering and removes active carbon, solvent evaporated is extracted with appropriate solvent, is washed, and it is dry, it is evaporated, with ethyl acetate and petroleum Ether volume ratio is 1: 5 column chromatographic purifying.Extracting the solvent used includes methylene chloride, chloroform, ethyl acetate.
In the step 3, third reaction dissolvent is glacial acetic acid, the mixed liquor of glacial acetic acid and tetrahydrofuran or glacial acetic acid and second The mixed liquor of nitrile；Reducing agent is zinc powder or iron powder；Wherein, the mixing of the glacial acetic acid (analysis is pure) and tetrahydrofuran (analysis is pure) The volume ratio of liquid is 1: 2~8；Preferably 1: 4；Glacial acetic acid (analysis is pure) and the volume ratio of the mixed liquor of acetonitrile (analysis is pure) are 1: 2~8；Preferably 1: 4.It is described after the reaction was completed further include: filter, solvent evaporated extracts with appropriate solvent, be added into system Saturated sodium carbonate solution adjusts pH to 8~9, is layered, and washes, dry, is evaporated, with concentrated hydrochloric acid at salt.Extracting the solvent used includes Methylene chloride, chloroform, ethyl acetate.
In the step 4, the 4th reaction dissolvent is isopropanol, n,N-Dimethylformamide or acetonitrile；The reaction is completed Afterwards further include: filter, solvent evaporated.Isopropanol and methanol volume ratio is used to carry out mashing purifying for 10: 1.
The beneficial effects of the present invention are: (1) present invention with 1- benzyl -4- (5- isopropoxy -2- methyl -4- nitrobenzene Base) -1,2,3,6- tetrahydropyridines are starting material, are reacted by nucleophilic displacement of fluorine, nitro reduction, deprotection, hydrolysis of ester group etc. To the chloro- N of Ceritinib analog 5-2(2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl)-N4-(2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride, synthetic route is brief, high income；(2) synthesis of the invention Method is related to easy to operate, and condition is easily-controllable；(3) agents useful for same of the present invention is cheap and easy to get, at low cost.
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail.Implement process of the invention, condition, Experimental method etc. is among the general principles and common general knowledge in the art in addition to what is specifically mentioned below, and the present invention does not have Especially limitation content.
Embodiment 1
1.1 compound I, that is, 2,2,2- trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- dihydro pyrrole The synthesis of pyridine -1 (2H)-carboxylic acid tert-butyl ester
By 1g 1- benzyl -4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -1,2,3,6- tetrahydro pyrrole in single port bottle Pyridine is dissolved in 7mL acetonitrile, and 0.58g trichloroethyl chloroformate, room temperature reaction is added.Reaction 2 hours, TLC detection raw material have reacted Entirely.It is evaporated acetonitrile, ethyl acetate and petroleum ether volume ratio is used to carry out column chromatographic purifying for 1: 8.Obtain compound I i.e. 2,2,2- Trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester 1.07g, Yield is 87%.
1H NMR:(500MHz,CDCl3) δ 7.64 (s, 1H), 6.80 (s, 1H), 5.67 (d, J=17.9Hz, 1H), 4.83 (s, 2H), 4.65-4.61 (m, 1H), 4.23 (d, J=23.2Hz, 2H), 3.80 (d, J=25.1Hz, 2H), 2.40 (br, 2H), 2.26 (s, 3H), 1.40 (d, J=6.1Hz, 6H)
13C NMR(126MHz,CDCl3)δ153.76,153.44,149.40,147.86,139.54,136.72, 136.56,127.29,126.93,123.54,122.99,116.39,95.61,75.16,75.09,72.88,43.77, 43.31,41.01,40.74,29.47,29.11,21.97,18.89。
1.2 compound I, that is, 2,2,2- trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- dihydro pyrrole The synthesis of pyridine -1 (2H)-carboxylic acid tert-butyl ester
By 1g 1- benzyl -4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -1,2,3,6- tetrahydro pyrrole in single port bottle Pyridine is dissolved in 7mL acetonitrile, and 0.58g trichloroethyl chloroformate is added, is warming up to 50 DEG C of reactions.Reaction 1 hour, TLC detect raw material Fully reacting.It is evaporated acetonitrile, ethyl acetate and petroleum ether volume ratio is used to carry out column chromatographic purifying for 1: 8.Obtain compound I i.e. 2,2,2- trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester 0.93g, yield 76%.
1H NMR:(500MHz,CDCl3) δ 7.64 (s, 1H), 6.80 (s, 1H), 5.67 (d, J=17.9Hz, 1H), 4.83 (s, 2H), 4.65-4.61 (m, 1H), 4.23 (d, J=23.2Hz, 2H), 3.80 (d, J=25.1Hz, 2H), 2.40 (br, 2H), 2.26 (s, 3H), 1.40 (d, J=6.1Hz, 6H)
13C NMR(126MHz,CDCl3)δ153.76,153.44,149.40,147.86,139.54,136.72, 136.56,127.29,126.93,123.54,122.99,116.39,95.61,75.16,75.09,72.88,43.77, 43.31,41.01,40.74,29.47,29.11,21.97,18.89。
1.3 compound I, that is, 2,2,2- trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- dihydro pyrrole The synthesis of pyridine -1 (2H)-carboxylic acid tert-butyl ester
By 1g 1- benzyl -4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -1,2,3,6- tetrahydro pyrrole in single port bottle Pyridine is dissolved in 7mL tetrahydrofuran, and 0.58g trichloroethyl chloroformate is added, is warming up to 40 DEG C of reactions.Reaction 1 hour, TLC detection Raw material fully reacting.It is evaporated tetrahydrofuran, ethyl acetate and petroleum ether volume ratio is used to carry out column chromatographic purifying for 1: 8.It obtains Compound I, that is, 2,2,2- trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-carboxylic Tert-butyl acrylate 0.99g, yield 80%.
1H NMR:(500MHz,CDCl3) δ 7.64 (s, 1H), 6.80 (s, 1H), 5.67 (d, J=17.9Hz, 1H), 4.83 (s, 2H), 4.65-4.61 (m, 1H), 4.23 (d, J=23.2Hz, 2H), 3.80 (d, J=25.1Hz, 2H), 2.40 (br, 2H), 2.26 (s, 3H), 1.40 (d, J=6.1Hz, 6H)
13C NMR(126MHz,CDCl3)δ153.76,153.44,149.40,147.86,139.54,136.72, 136.56,127.29,126.93,123.54,122.99,116.39,95.61,75.16,75.09,72.88,43.77, 43.31,41.01,40.74,29.47,29.11,21.97,18.89。
Embodiment 2
2.1 compound II, that is, 2,2,2- trichloroethyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- dihydro The synthesis of pyridine -1 (2H)-carboxylic acid tert-butyl ester
By 4.0g 2,2,2- trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- two in single port bottle Pyridinium hydroxide -1 (2H)-carboxylic acid tert-butyl ester is dissolved in 40mL dehydrated alcohol, and 0.29g ferric trichloride is added, and adds 0.58g activity Charcoal adds 50% hydrazine hydrate of 10.64g, is warming up to 75 DEG C.Reaction 6 hours, TLC detect raw material fully reacting.Pad diatomite It filters, is evaporated dehydrated alcohol, methylene chloride is added, is washed twice with water, separate organic phase, anhydrous sodium sulfate is dry, is evaporated, adopts Column chromatographic purifying is carried out with ethyl acetate and petroleum ether volume ratio for 1: 5.Obtain compound II i.e. 2,2,2- trichloroethyl 4- (4- Amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester 3.2g, yield 86%.
1H NMR:(500MHz,CDCl3) δ 6.56 (s, 2H), 5.56 (d, J=17.5Hz, 1H), 4.83 (s, 2H), 4.51- 4.47 (m, 1H), 4.18 (d, J=23.3Hz, 2H), 3.79-3.72 (m, 4H), 2.41 (br, 2H), 2.16 (s, 3H), 1.36 (d, J=6.1Hz, 6H)
13C NMR(126MHz,CDCl3)δ153.87,153.52,143.26,137.89,137.75,136.02, 132.35,127.34,121.68,121.15,117.27,114.02,95.75,75.13,75.05,71.03,43.98, 43.48,41.32,41.10,30.32,29.96,22.37,19.29。
2.2 compound II, that is, 2,2,2- trichloroethyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- dihydro The synthesis of pyridine -1 (2H)-carboxylic acid tert-butyl ester
By 4.0g 2,2,2- trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- two in single port bottle Pyridinium hydroxide -1 (2H)-carboxylic acid tert-butyl ester is dissolved in 40mL anhydrous methanol, and 0.29g ferric trichloride is added, and adds 0.58g activity Charcoal adds 50% hydrazine hydrate of 10.64g, is warming up to 75 DEG C.Reaction 8 hours, TLC detect raw material fully reacting.Pad diatomite It filters, is evaporated dehydrated alcohol, methylene chloride is added, is washed twice with water, separate organic phase, anhydrous sodium sulfate is dry, is evaporated, adopts Column chromatographic purifying is carried out with ethyl acetate and petroleum ether volume ratio for 1: 5.Obtain compound II i.e. 2,2,2- trichloroethyl 4- (4- Amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester 2.97g, yield 80%.
1H NMR:(500MHz,CDCl3) δ 6.56 (s, 2H), 5.56 (d, J=17.5Hz, 1H), 4.83 (s, 2H), 4.51- 4.47 (m, 1H), 4.18 (d, J=23.3Hz, 2H), 3.79-3.72 (m, 4H), 2.41 (br, 2H), 2.16 (s, 3H), 1.36 (d, J=6.1Hz, 6H)
13C NMR(126MHz,CDCl3)δ153.87,153.52,143.26,137.89,137.75,136.02, 132.35,127.34,121.68,121.15,117.27,114.02,95.75,75.13,75.05,71.03,43.98, 43.48,41.32,41.10,30.32,29.96,22.37,19.29。
2.3 compound II, that is, 2,2,2- trichloroethyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- dihydro The synthesis of pyridine -1 (2H)-carboxylic acid tert-butyl ester
By 4.0g 2,2,2- trichloroethyl 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- two in single port bottle Pyridinium hydroxide -1 (2H)-carboxylic acid tert-butyl ester is dissolved in 40mL dehydrated alcohol, and 0.15g ferric trichloride is added, and adds 0.58g activity Charcoal adds 50% hydrazine hydrate of 10.64g, is warming up to 75 DEG C.Reaction 12 hours, TLC detect raw material fully reacting.Pad diatomite It filters, is evaporated dehydrated alcohol, methylene chloride is added, is washed twice with water, separate organic phase, anhydrous sodium sulfate is dry, is evaporated, adopts Column chromatographic purifying is carried out with ethyl acetate and petroleum ether volume ratio for 1: 5.Obtain compound II i.e. 2,2,2- trichloroethyl 4- (4- Amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester 2.80g, yield 75%.
1H NMR:(500MHz,CDCl3) δ 6.56 (s, 2H), 5.56 (d, J=17.5Hz, 1H), 4.83 (s, 2H), 4.51- 4.47 (m, 1H), 4.18 (d, J=23.3Hz, 2H), 3.79-3.72 (m, 4H), 2.41 (br, 2H), 2.16 (s, 3H), 1.36 (d, J=6.1Hz, 6H)
13C NMR(126MHz,CDCl3)δ153.87,153.52,143.26,137.89,137.75,136.02, 132.35,127.34,121.68,121.15,117.27,114.02,95.75,75.13,75.05,71.03,43.98, 43.48,41.32,41.10,30.32,29.96,22.37,19.29。
Embodiment 3
3.1 compound III, that is, 2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline dihydrochlorides Synthesis
By 1.92g 2,2,2- trichloroethyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- in single port bottle Dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester is dissolved in 15mL in the mixed solvent (V (acetonitrile): V (glacial acetic acid)=4: 1), and 9.6g is added Zinc powder, room temperature reaction.Reaction 4 hours, TLC detect raw material fully reacting.Suction filtered through kieselguhr is padded, reaction dissolvent is evaporated, to system Middle addition saturated sodium carbonate solution tune pH to 9~10, is extracted with dichloromethane, and washing, anhydrous sodium sulfate is dry, is evaporated.By institute It obtains compound to be dissolved in 5mL anhydrous methanol, 0.57mL concentrated hydrochloric acid is added, 20min is stirred at room temperature, is evaporated anhydrous methanol, is changed Object III, that is, 2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline dihydrochloride 1.25g is closed, yield is 86%.
1H NMR:(500MHz,DMSO-d6)δ10.08(br,2H),9.69(s,2H),7.25(s,1H),6.89(s,1H), 5.59 (s, 1H), 4.69-4.64 (m, 1H), 3.66 (br, 4H), 3.25 (br, 2H), 2.19 (s, 3H), 1.29 (d, J= 6.0Hz,6H).
13C NMR(126MHz,DMSO-d6)δ148.66,142.05,136.42,127.34,125.85,120.96, 120.08,114.50,71.51,41.28,26.35,22.16,19.17。
3.2 compound III, that is, 2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline dihydrochlorides Synthesis
By 1.92g 2,2,2- trichloroethyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- in single port bottle Dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester is dissolved in 15mL glacial acetic acid solution, and 9.6g zinc powder, room temperature reaction is added.It is small to react 6 When, TLC detects raw material fully reacting.Suction filtered through kieselguhr is padded, reaction dissolvent is evaporated, saturated sodium carbonate solution tune is added into system PH to 9~10, is extracted with dichloromethane, and washing, anhydrous sodium sulfate is dry, is evaporated.Gained compound is dissolved in 5mL anhydrous methanol In, 0.57mL concentrated hydrochloric acid is added, 20min is stirred at room temperature, is evaporated anhydrous methanol, obtains compound III i.e. 2- isopropoxy -5- first Base -4- (1,2,3,6- tetrahydropyridine -4- base) aniline dihydrochloride 1.03g, yield 71%.
1H NMR:(500MHz,DMSO-d6)δ10.08(br,2H),9.69(s,2H),7.25(s,1H),6.89(s,1H), 5.59 (s, 1H), 4.69-4.64 (m, 1H), 3.66 (br, 4H), 3.25 (br, 2H), 2.19 (s, 3H), 1.29 (d, J= 6.0Hz,6H).
13C NMR(126MHz,DMSO-d6)δ148.66,142.05,136.42,127.34,125.85,120.96, 120.08,114.50,71.51,41.28,26.35,22.16,19.17。
3.3 compound III, that is, 2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline dihydrochlorides Synthesis
By 1.92g 2,2,2- trichloroethyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- in single port bottle Dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester is dissolved in 15mL in the mixed solvent (V (tetrahydrofuran): V (glacial acetic acid)=4: 1), is added 9.6g activated zinc powder, room temperature reaction.Reaction 7 hours, TLC detect raw material fully reacting.Suction filtered through kieselguhr is padded, it is molten to be evaporated reaction Saturated sodium carbonate solution tune pH to 9~10 is added into system, is extracted with dichloromethane for agent, washes, and anhydrous sodium sulfate is dry, It is evaporated.Gained compound is dissolved in 5mL anhydrous methanol, 0.57mL concentrated hydrochloric acid is added, 20min is stirred at room temperature, is evaporated no water beetle Alcohol obtains compound III i.e. 2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline dihydrochloride 1.09g, yield 75%.
1H NMR:(500MHz,DMSO-d6)δ10.08(br,2H),9.69(s,2H),7.25(s,1H),6.89(s,1H), 5.59 (s, 1H), 4.69-4.64 (m, 1H), 3.66 (br, 4H), 3.25 (br, 2H), 2.19 (s, 3H), 1.29 (d, J= 6.0Hz,6H).
13C NMR(126MHz,DMSO-d6)δ148.66,142.05,136.42,127.34,125.85,120.96, 120.08,114.50,71.51,41.28,26.35,22.16,19.17。
Embodiment 4
4.1 compounds V are the chloro- N of 5-2(2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl) - N4The synthesis of (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride
By 1.04g2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline disalt in single port bottle Hydrochlorate is dissolved in 14mL isopropanol, and 1.57g2, the chloro- N- of 5- bis- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine, heating is added To 90 DEG C of back flow reactions.Reaction 10 hours, TLC detect raw material fully reacting.It is cooled to room temperature, filters, solid uses isopropanol: Methanol volume ratio 10: 1 carries out mashing purifying.Obtain the chloro- N of compound V i.e. 5-2(2- isobutyl group -5- methyl -4- (1,2,3,6- Tetrahydropyridine -4- base) phenyl)-N4(2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride 1.53g, yield It is 75%.
1H NMR:(600MHz,DMSO-d6) δ 8.26 (s, 1H), 8.01 (br, 1H), 7.89 (d, J=7.9Hz, 1H), 7.71 (t, J=7.7Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 5.51 (s, 1H), 4.53-4.49 (m, 1H), 3.66 (s, 2H), 3.40-3.36 (m, 1H), 3.28 (t, J=5.7Hz, 2H), 2.43 (s, 2H), 1.93 (s, 3H), 1.18 (d, J=5.9Hz, 6H), 1.09 (d, J=6.7Hz, 6H)
13C NMR(126MHz,DMSO-d6)δ158.23,152.93,146.12,137.87,136.80,136.67, 135.59,131.75,129.90,128.19,127.38,126.74,126.50,123.46,119.71,113.97,105.01, 71.68,62.46,54.86,41.36,26.44,25.95,22.17,19.78,15.23。
4.2 compounds V are the chloro- N of 5-2(2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl) - N4The synthesis of (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride
By 1.04g2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline disalt in single port bottle Hydrochlorate is dissolved in 14mL isopropanol, and 1.12g 2 is added, and the chloro- N- of 5- bis- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine rises Temperature is to 90 DEG C of back flow reactions.Reaction 10 hours, TLC detect raw material fully reacting.It is cooled to room temperature, filters, solid uses isopropyl Alcohol: methanol volume ratio 10: 1 carries out mashing purifying.Obtain the chloro- N of compound V i.e. 5-2(2- isobutyl group -5- methyl -4- (1,2,3, 6- tetrahydropyridine -4- base) phenyl)-N4(2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride 1.38g is received Rate is 68%.
1H NMR:(600MHz,DMSO-d6) δ 8.26 (s, 1H), 8.01 (br, 1H), 7.89 (d, J=7.9Hz, 1H), 7.71 (t, J=7.7Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 5.51 (s, 1H), 4.53-4.49 (m, 1H), 3.66 (s, 2H), 3.40-3.36 (m, 1H), 3.28 (t, J=5.7Hz, 2H), 2.43 (s, 2H), 1.93 (s, 3H), 1.18 (d, J=5.9Hz, 6H), 1.09 (d, J=6.7Hz, 6H)
13C NMR(126MHz,DMSO-d6)δ158.23,152.93,146.12,137.87,136.80,136.67, 135.59,131.75,129.90,128.19,127.38,126.74,126.50,123.46,119.71,113.97,105.01, 71.68,62.46,54.86,41.36,26.44,25.95,22.17,19.78,15.23。
4.3 compounds V are the chloro- N of 5-2(2- isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl) - N4The synthesis of (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride
By 1.04g2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline disalt in single port bottle Hydrochlorate is dissolved in 14mL isopropanol, and 1.57g 2 is added, and the chloro- N- of 5- bis- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine rises Temperature is to 110 DEG C of back flow reactions.Reaction 8 hours, TLC detect raw material fully reacting.It is cooled to room temperature, filters, solid uses isopropyl Alcohol: methanol volume ratio 10: 1 carries out mashing purifying.Obtain the chloro- N of compound V i.e. 5-2(2- isobutyl group -5- methyl -4- (1,2,3, 6- tetrahydropyridine -4- base) phenyl)-N4(2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride 1.23g is received Rate is 60%.
1H NMR:(600MHz,DMSO-d6) δ 8.26 (s, 1H), 8.01 (br, 1H), 7.89 (d, J=7.9Hz, 1H), 7.71 (t, J=7.7Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 5.51 (s, 1H), 4.53-4.49 (m, 1H), 3.66 (s, 2H), 3.40-3.36 (m, 1H), 3.28 (t, J=5.7Hz, 2H), 2.43 (s, 2H), 1.93 (s, 3H), 1.18 (d, J=5.9Hz, 6H), 1.09 (d, J=6.7Hz, 6H)
13C NMR(126MHz,DMSO-d6)δ158.23,152.93,146.12,137.87,136.80,136.67, 135.59,131.75,129.90,128.19,127.38,126.74,126.50,123.46,119.71,113.97,105.01, 71.68,62.46,54.86,41.36,26.44,25.95,22.17,19.78,15.23。
In conclusion the present invention prepares the chloro- N of Ceritinib analog i.e. 5-2(2- isobutyl group -5- methyl -4- (1,2,3, 6- tetrahydropyridine -4- base) phenyl)-N4The method of (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamine dihydrochloride has Have the advantages that synthetic route is brief, easy to operate, at low cost, yield is high.
Protection content of the invention is not limited to above embodiments.Without departing from the spirit and scope of the invention, originally Field technical staff it is conceivable that variation and advantage be all included in the present invention, and with appended claims be protect Protect range.

Claims (6)

1. a kind of preparation method of Ceritinib analog, which is characterized in that this method comprising the following specific steps
Step 1: 1- benzyl -4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -1,2,3,6- tetrahydropyridine is added first In reaction dissolvent, nucleophilic substitution occurs with trichloroethyl chloroformate, obtains 2,2,2- trichloroethyl 4- (5- isopropoxies- 2- methyl -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester, that is, compound I；Wherein, (5- is different by 1- benzyl -4- Propoxyl group -2- methyl -4- nitrobenzophenone) the ratio between the mole of -1,2,3,6- tetrahydropyridine and trichloroethyl chloroformate is 1: 1.0 ~1.5, reaction temperature is 10~50 DEG C, and the time of reaction is 1~4 hour；
Step 2: by compound I made from step 1 be dissolved in the second reaction dissolvent with ferric trichloride, active carbon, hydration hydrazine reaction, Obtain 2,2,2- trichloroethyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) -3,6- dihydropyridine -1 (2H)-carboxylic acid uncle Butyl ester, that is, compound II；Wherein, the ratio between mole of the compound I and ferric trichloride, active carbon, hydrazine hydrate for 1: 0.1~ 0.5: 2~10: 5~20；Reaction temperature is 50~80 DEG C；The time of reaction is 4~15 hours；
Step 3: compound II made from step 2 being added in third reaction dissolvent, reducing agent is added and carries out deprotection reaction, obtains To 2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) aniline dihydrochloride, that is, compound III；Wherein, institute Stating the ratio between mole of compound II and reducing agent is 1: 10~35, and reaction temperature is 10~50 DEG C, and the time of reaction is 2~8 Hour；
Step 4: by compound III made from step 3 and the chloro- N- of 2,5- bis- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine I.e. compounds Ⅳ is dissolved in the 4th reaction dissolvent, generates the chloro- N of the Ceritinib analog 5- by nucleophilic substitution2-(2- Isobutyl group -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- base) phenyl)-N4(2- (isopropelsulfonyl) phenyl) pyrimidine -2, 4- diamine dihydrochloride, that is, compound V；Wherein, the ratio between mole of the compound III and compounds Ⅳ be 1: 1.0~ 1.5, reaction temperature is 75~110 DEG C, and the time of reaction is 6~20 hours；Specific synthesis process is shown below:
2. synthetic method according to claim 1, which is characterized in that in the step 1, the first reaction dissolvent is N, N- bis- Methylformamide, tetrahydrofuran or acetonitrile；It is described after the reaction was completed further include: solvent evaporated, column chromatographic purifying.
3. synthetic method according to claim 1, which is characterized in that in the step 2, the second reaction dissolvent is anhydrous second Alcohol, anhydrous methanol or tetrahydrofuran；It is described after the reaction was completed further include: filter, solvent evaporated is washed with water, methylene chloride extraction It takes, drying is evaporated, column chromatographic purifying.
4. synthetic method according to claim 1, which is characterized in that in the step 3, third reaction dissolvent is ice vinegar The mixed liquor of acid, the mixed liquor or glacial acetic acid of glacial acetic acid and tetrahydrofuran and acetonitrile；Reducing agent is zinc powder or iron powder；The reaction After the completion further include: filter, solvent evaporated, adjust pH with basic solvent, be extracted with dichloromethane, wash, drying is evaporated, and use is dense Hydrochloric acid is at salt.
5. synthetic method according to claim 1, which is characterized in that in the step 4, the 4th reaction dissolvent is isopropyl Alcohol, N,N-dimethylformamide or acetonitrile；It is described after the reaction was completed further include: filter, with isopropanol be beaten purify, filter.
6. synthetic method according to claim 4, which is characterized in that the body of the mixed liquor of the glacial acetic acid and tetrahydrofuran Product is than being 1: 2~8；The volume ratio of the mixed liquor of glacial acetic acid and acetonitrile is 1: 2~8；The glacial acetic acid, tetrahydrofuran and acetonitrile are It analyzes pure.
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