CN104447515B - Prepare new intermediate of Ceritinib and preparation method thereof - Google Patents
Prepare new intermediate of Ceritinib and preparation method thereof Download PDFInfo
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- CN104447515B CN104447515B CN201410625539.6A CN201410625539A CN104447515B CN 104447515 B CN104447515 B CN 104447515B CN 201410625539 A CN201410625539 A CN 201410625539A CN 104447515 B CN104447515 B CN 104447515B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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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
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Abstract
The present invention relates to be used to prepare compound 1 shown in the intermediate formula (1) of Ceritinib and the compound 2 shown in formula (2), or compound 2 chemically acceptable salt.Wherein, R is saturation or unsaturated aromatic ring methylene, the benzyl position form group of heteroaromatic methylene；X is halogen.The invention further relates to a kind of by new intermediate compound 1 and the method for the prepare compound 4 of compound 2, wherein, boron hydride or its composition and alcohols solvent are used by the reduction step of compound 1 to compound 2；By catalytic hydrogenation or transfer hydrogenation process reducing compound 2, compound 4 is generated.The route by the prepare compound 4 of compound 1 and 2 that the present invention is provided, chemical reduction step is combined with catalytic hydrogenation, it is to avoid using expensive platinum dioxide, significantly reduce the cost of the intermediate 4 for synthesizing Ceritinib.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to one kind is for preparing Remedies for lung cancer thing Ceritinib
The new intermediate of (ceritinib, LDK378) and preparation method thereof.
Background technology
Lung cancer is one of global incidence highest malignant tumour, and due to the influence of the various factors such as environment, its morbidity
Rate is increased with the speed per year over 3%.And have 80-85% in the patients with lung cancer made a definite diagnosis is non-small cell lung
Cancer (NSCLC), wherein 2%-7% cases are driven by the rearrangement (rearrangement) of ALK gene, cause adding for cancer cell
Fast-growing is long, and sb.'s illness took a turn for the worse.Ceritinib is a kind of oral, anaplastic lymphoma kinase (ALK) inhibitor, is being controlled in clinical research
Breakthrough is achieved in treatment Metastatic Nsclc (NSCLC) patient.The U.S.'s food and medicine of on April 29th, 2014 is supervised
Superintend and direct after management board [FDA] have approved Ceritinib for being treated through Xalkori (crizotinib) that sb.'s illness took a turn for the worse or to Xalkori
The treatment of the anaplastic lymphoma kinase positive (ALK+) Metastatic Nsclc (NSCLC) patient not tolerated.Color is auspicious to be replaced
Buddhist nun has quick, the antitumor action of lasting and high activity to ALK+NSCLC patient.
In current published document [J.Med.Chem.2013,56,5675-5690], Ceritinib preparation method is such as
Under：
Wherein, the synthesis of key intermediate 4 is a very important synthesis step.According to patent document
WO2008073687A2 is recorded, and is needed during synthetic intermediate 4 using the expensive platinum dioxide of 40% (weight ratio)
It is catalyzed, is hydrogenated with 36 hours, yield is only 60%.The cost of wherein platinum dioxide catalyst is occupied and prepares Ceritinib
Cost of material it is only about half of more than, cause final product cost very expensive, be unfavorable for meeting the use of broad masses of the people
Medicine demand.Therefore, find the synthetic route that cost is lower, finished product purity is higher and prepare key intermediate 4, it is existing to substitute
Ceritinib synthetic route is significant.
The content of the invention
It is an object of the invention to provide a kind of new intermediate for preparing Ceritinib and preparation method thereof, utilize
The process route of this intermediate synthesis Ceritinib is simple, and low raw-material cost is adapted to industrialized production, improves product purity,
Reduce product cost.
The cost of known platinum dioxide catalyst is 30-40 times of palladium-carbon catalyst cost, but general palladium carbon catalysis
Agent can not be by the pyridine reduction in above-claimed cpd.Compound 3 is prepared into season by the present inventor by being found after substantial amounts of trial
After ammonium salt compound 1, the quaternary ammonium salt of pyridine ring can be reduced by sodium borohydride, potassium borohydride etc..Changed into by by pyridine
Quaternary ammonium form can reduce the condition of reduction pyridine aromatic ring.Compound 1 can be change by sodium borohydride, potassium borohydride reduction
Compound 2.The inventors discovered that, boron hydride (such as sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride) can be by chemical combination
The pyridine ring of thing 1 is restored to compound 2.Double bond and benzyl in compound 2 can be reduced to piperidines by conventional palladium carbon
Compound 4.Wherein compound 4 is to prepare Ceritinib key intermediate.The present invention is by chemical reduction step and palladium carbon catalytic hydrogenation
It is combined, significantly reduces the cost of the intermediate 4 of synthesis Ceritinib, the preparation cost for solving key intermediate 4 is high
Problem.Specific synthetic route is as follows：
Wherein, the quarternary ammonium salt compound 1 is the quaternary ammonium salt of the benzyl position form group containing aromatic ring or heteroaromatic；It is preferred that
Ground, the quaternary ammonium salt is benzyl quaternary ammonium salt, can be obtained with the reaction of compound 3 by corresponding halogenation benzyl (benzyl position halide).
In the present invention, R includes the benzyl position form group of substituted or unsubstituted aromatic ring methylene, heteroaromatic methylene, wherein, the virtue
Ring is C6-C10Aromatic ring, the heteroaromatic is at least to contain selected from heteroatomic 5 to 8 yuan of heteroaromatic in N, S or O, described
Substitution base is hydroxyl, halogen, amino, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl group, C1-C6Alkyl oxycarbonyl
Base, C1-C6Alkyl amine group, C1-C4One or more in alkyl-carbonyl；Preferably, R is that unsubstituted benzyl (or is benzene first
Base) or the substituted base of phenyl ring upper band benzyl, the benzhydryl of unsubstituted benzhydryl or the substituted base of phenyl ring upper band,
Or the menaphthyl of unsubstituted menaphthyl or the substituted base of naphthalene nucleus upper band；X is halogen.Compound 2 can be further with HA
It is made the chemically acceptable salt (referred to as 2 salt) being shown below：
Wherein, the HA is chemically acceptable organic acid or inorganic acid.Described its chemically acceptable salt is
Chemically acceptable acylate or inorganic acid salt, the inorganic acid salt are hydrochloride, hydrobromate, hydriodate, acetic acid
Salt, sulfate or disulfate, phosphate or hydrophosphate or dihydric phosphate；Acylate is formates, acetate, propionic acid
Salt, butyrate, oxalates, fumarate, maleate, succinate, tartrate, mandelate, methane sulfonates, benzene sulphur
Hydrochlorate, tosilate or camsilate.
Wherein, the preparation of compound 3, may be referred to literature method (CN101616895A) preparation.
The preparation of compound 1, using compound 3 and the corresponding benzyl position halide reaction corresponding quaternary ammonium salt of generation.Wherein,
Benzyl position halide is the benzyl position halide of substituted or unsubstituted aromatic ring or heteroaromatic, wherein, the aromatic ring is C6-C10Virtue
Ring, the heteroaromatic is that the substitution base is hydroxyl at least containing selected from heteroatomic 5 to 8 yuan of heteroaromatic in N, S or O
Base, halogen, amino, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl group, C1-C6Alkoxy, C1-C6Alkyl
Carbonyl, C1-C6Alkyl amine group, C1-C4One or more in alkyl-carbonyl；Preferably, benzyl position halide is benzyl chloride, bromine
Benzyl, a fluorobenzyl chloride, iodine benzyl, 2- chloromethyl naphthalenes, 2- bromomethyls naphthalene, 1 chloromethyl naphthalene or 1- bromomethyl naphthalenes.
The inventors discovered that compound 1 can be by boron hydride (such as sodium borohydride, potassium borohydride, lithium borohydride, hydroboration
Zinc) or its composition reduction, corresponding 3- alkene piperidines (i.e. compound 2) is generated, the various benzyl protecting groups in compound 2 are
In the various benzyls that subsequent step can be removed by catalytic hydrogenation.Wherein, can be obtained if compound 2 is further reduced
Corresponding N-protected piperidine compounds 5, shown in following reaction equation.Compound 1 uses borohydride reduction condition of the invention, obtains
To be substantially pure compound 2, a certain proportion of compound 5 may be contained.Compound 2 and compound 5 can be connect down
The catalytic hydrogenation removing benzyl protecting group for coming, generates the important intermediate compound 4 for preparing Ceritinib.Following institute
Show.
Reaction condition compound 1 being converted into used by the reduction reaction of compound is that boron hydride and alcohols are molten
Agent.Preferably, the boron hydride is sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride or its composition；It is described
Alcohols solvent is conventional C1~C6Low carbon chain alcohol, or its composition, such as methyl alcohol, ethanol, propyl alcohol, isopropanol, butanol,
Isobutanol, amylalcohol, 2- amylalcohols, hexanol etc..Reaction temperature is -20 DEG C to 60 DEG C.
The method of the debenzylation of compound 2, can use catalytic hydrogenation, or the method such as transfer hydrogenation, and catalyst can be with
It is palladium carbon, ruthenium carbon etc..Certainly valuable rhodium carbon and platinum carbon, also there is the same function.Hydrogen source can be hydrogen, it would however also be possible to employ turn
Move hydrogenation, such as ammonium formate, formic acid etc..Compound of the present invention 1 and 2 can be used to prepare important intermediate compound 4.Chemical combination
Thing 4, or compound 4 hydrochloride, or compound 4 N-BOC protection intermediate, can be used in and pyrimidine intermediate
Compound is coupled, and obtains Ceritinib (Ceritinib, or LDK-378).General scheme is as follows:
The route of the prepare compound 4 by new intermediate 1 and 2 that the present invention is provided, it is to avoid use expensive dioxy
Change platinum, significantly reduce the production cost of key intermediate 4, the Material Cost for preparing Ceritinib can be greatly reduced, from
And provide a kind of new method for final products Ceritinib cost is greatly reduced.In addition, the compound 4 that the route is obtained is pure
Degree is high, and the final all single contaminants of bulk drug are not higher than 0.1%, may finally prepare the Ceritinib of high-purity.
Specific embodiment
The following examples can make those skilled in the art that the present invention is more fully understood, but it is limited never in any form
The present invention.
The preparation of the fluoro- 5- nitro-toluenes of the chloro- 4- of the 2- of embodiment 1.
The 135ml concentrated sulfuric acids are put into reaction bulb, the lower ice bath cooling of stirring is added dropwise 43.4g fuming nitric aicds.Continue to stir after dripping off
30min is mixed, nitration mixture is formed.The 315ml concentrated sulfuric acids (3.5V) and the fluoro- first of the chloro- 4- of 90.0g2- are put into another there-necked flask simultaneously
Benzene.Under ice salt bath cooling, during the nitration mixture that above-mentioned nitric acid and sulfuric acid are constituted added into the sulfuric acid liquid of the 2- fluoro- toluene of chloro- 4-, continue anti-
Answer 1~2 hour.Reaction solution is slowly added under stirring be quenched in trash ice, ethyl acetate is extracted twice.Combined ethyl acetate, uses
Twice, saturated brine washed once water washing.Organic phase is concentrated to dryness, and obtains the fluoro- 5- nitro-toluenes of the chloro- 4- of grease 2-.
1H NMR(CDCl3):δ7.95(d,3.8,1H),7.51(d,4.2,1H),2.45(s,3H)。
The preparation of the chloro- 4- isopropoxies -5- nitro-toluenes of the 2- of embodiment 2.
The fluoro- 5- nitro-toluenes of the chloro- 4- of 2- are dissolved with 1200ml isopropanols and 2L there-necked flasks are added.Add 429g anhydrous
Potassium carbonate powder.Backflow is warming up under stirring.Maintain the reflux for lower reaction~40 hour.Concentration removes most of isopropanol.Add
2L water, is extracted with ethyl acetate twice.Combined ethyl acetate layer, washing.Concentration ethyl acetate, obtains the chloro- 4- isopropyls oxygen of brown 2-
Base -5- nitro-toluenes.
1H NMR(CDCl3):δ7.71(s,1H),7.07(s,1H),4.61(m,1H),2.34(s,3H),1.40(d,
3.2,6H)。
The preparation of the 4- of embodiment 3. (5- isopropoxy -2- methyl -4- nitro-phenyls) pyridine
By chloro- 4- isopropoxies -5- nitro-toluenes 78g, 4- pyridine boronic acids 42g of 2-, potassium carbonate 97g, dioxane
780mL, purified water 390mL, palladium 7.67g, triphenylphosphine 35.85g are added in 2L three-necked bottles.Nitrogen is protected, and is stirred at reflux
Reaction 24 hours.Concentration removes most of dioxane.1.5L water, ethyl acetate is added to be extracted twice.Merge acetic acid second
Ester, is washed twice with saturated aqueous common salt, and organic phase is concentrated to dryness, obtain brown solid 4- (5- isopropoxy -2- methyl -4- nitros -
Phenyl) pyridine, i.e. compound 3.
1H NMR(CDCl3):δ8.72(m,2H),7.71(s,1H),7.31(m,2H),6.89(s,1H),4.63(m,
1H),2.21(s,3H),1.38(d,3.0,6H)。
The preparation of the 4- of embodiment 4. (5- isopropoxy -2- methyl -4- nitro-phenyls) -1- benzyls-pyridinium bromide
By 4- (5- isopropoxy -2- methyl -4- nitro-phenyls) pyridine (33g), bromobenzyl (31.08g), tetrahydrofuran
(330mL) is added in 1000mL reaction bulbs.Stirring, heating reflux reaction is overnight.It is cooled to normal temperature.It is slowly added to heptane
330mL.Continue to stir 1 hour, filtering.Filter cake is dried, and obtains 4- (5- isopropyl -2- methyl -4- nitro-phenyls) -1- benzyls-bromine
Change pyridine.Purity 99%.
MS(ESI+):363.2(M)+。1H NMR(DMSO-d6):δ9.40(d,3.4,2H),8.33(d,3.4,2H),7.89
(s,1H),7.65-7.68(m,2H),7.45-7.51(m,3H),7.43(s,1H),5.96(s,2H),4.84-4.88(m,1H),
2.25(s,3H),1.27(d,3.0.6H)。
2- isopropoxy -5- methyl-the 4- of embodiment 5. (1- benzyl -1,2,3,6- tetrahydropyridine -4- bases)-phenyl amine
Prepare
By 4- (5- isopropoxy -2- methyl -4- nitro-phenyls) -1- benzyls-pyridinium bromides (17.8g) and methyl alcohol
(535mL) is added in 1000mL reaction bulbs.Stirring, cooling.It is dividedly in some parts NaBH4(15.13g).It is slowly added to the hydrochloric acid of 3N
9mL.Confirm without NaBH4Residual.Solvent is evaporated off.Add water 190mL, stirring.Add ethyl acetate (190mL).Divide liquid, collect organic
Phase, water mutually continues to be extracted with ethyl acetate (190mL × 2).Merge organic phase, respectively be washed once with water and saturated aqueous common salt
(190mL).Organic phase is evaporated to obtain 2- isopropoxy -5- methyl -4- (1- benzyl -1,2,3,6- tetrahydropyridine -4- bases)-phenyl
Amine.
MS(ESI+):337.3(M+1)+。1H NMR(CDCl3):δ7.26-7.44(m,5H),6.59(s,1H),6.53(s,
1H),5.50(m,1H),4.44(m,1H),3.72(s,2H),3.19-3.24(m,2H),2.72-2.80(m,2H),2.41-
2.44(m,2H),2.16(m,3H),1.33(d,3.0,6H)。
2- isopropoxy -5- methyl-the 4- of embodiment 6. (1- benzyl -1,2,3,6- tetrahydropyridine -4- bases)-phenyl amine salt
The preparation of hydrochlorate
2- isopropoxy -5- methyl -4- (1- benzyl -1,2,3,6- tetrahydropyridine -4- bases)-phenyl amine (12.5g) is molten
In 125mL isopropanols, cooling is added dropwise isopropanol solution of hydrogen chloride to pH=1.Filtering, collect filter cake, be vacuum dried 2- is different
Propoxyl group -5- methyl -4- (1- benzyl -1,2,3,6- tetrahydropyridine -4- bases)-phenylamine hydrochloride.Purity 99%.
MS(ES+):337.3(M+1)+。1H NMR(DMSO-d6):δ7.71-7.74(m,2H),7.45-7.47(m,3H),
7.22(s,1H),6.90(s,1H),5.56(s,2H),4.65-4.68(m,1H),4.36-4.46(m,2H),3.60-3.72(m,
2H),3.51-3.54(m,1H),3.20-3.22(m,1H),2.85-2.89(m,1H),2.20(s,1H),1.28(d,2.86H)。
The preparation of embodiment 7. 2- isopropoxy -5- methyl -4- (piperidin-4-yl) aniline dihydrochloride
By 2- isopropoxy -5- methyl -4- (1- benzyl -1,2,3,6- tetrahydropyridine -4- bases)-phenyl amine (11.9g), first
Alcohol (119mL) is added in hydriding reactor.Nitrogen protection displacement.90 degree are heated to, 1.0MPa is forced into.Reaction 8 hours.It is cooled to
Normal temperature, Filtration of catalyst.Filtrate steaming removal solvent, adds isopropanol 119g.Ice bath cooling is lower to be added dropwise hydrochloric acid aqueous isopropanol,
Adjust pH to acidity.Filtering, filter cake is washed with isopropanol (12mL).Dry to obtain 2- isopropoxy -5- methyl -4- (piperidines -4-
Base) aniline dihydrochloride.Purity 99%.
MS(ESI+):249.3(M+1)+。1H NMR(DMSO-d6):δ7.18(s,1H),6.92(s,1H),4.62-4.65
(m,1H),3.29(d,4.8,2H),2.97-3.03(m,3H),2.22(s,1H),1.97-2.00(m,2H),1.76(d,5.2,
2H),1.29(d,2.4,6H)。
The chloro- N- of the 5- of embodiment 8. (2- isopropoxy -5- methyl -4- (piperidin-4-yl phenyl)-N-2- (isopropyl sulphonyl
Base) phenyl) -2,4- diamine dihydrochlorides preparation
By 2- isopropoxies -5- methyl -4- (piperidin-4-yl) aniline dihydrochloride (17.00g) and the chloro- N- (2- of 2,5- bis-
(isopropelsulfonyl) phenyl) during pyrimidine -4- amine (commercially available) (18.32g) adds 500mL there-necked flasks, add isopropanol 170mL.
Agitating heating back flow reaction is overnight.Filtering, washing after room temperature are cooled to, filter cake is collected.Filtration cakes torrefaction obtains 5- chloro- N- (2- isopropyls
Epoxide -5- methyl -4- (piperidin-4-yl phenyl)-N-2- (isopropelsulfonyl) phenyl) -2,4- diamine dihydrochlorides.Purity
99%.
MS(ESI+):558.1(M+1)+。1H NMR(DMSO-d6):δ10.15(s,1H),9.18-9.38(m,3H),8.54
(s,1H),8.06-8.08(m,1H),7.92-7.94(d,3.2,1H)7.73-7.77(t,3.8,1H),7.54-7.58(t,
4.0,1H),7.31(s,1H),6.82(s,1H),4.51-4.57(m,1H),3.45-3.52(m,1H),3.30-3.32(d,
5.8,2H),2.93-3.03(m,3H),1.89-1.99(m,5H),1.73-1.77(d,6.4,2H),1.24-1.26(d,3.2,
6H),1.10-1.111(d,3.2,6H)。
The chloro- N- of the 5- of embodiment 9. (2- isopropoxy -5- methyl -4- (piperidin-4-yl phenyl)-N-2- (isopropyl sulphonyl
Base) phenyl) -2,4- diamines (LDK-378) preparation
By the chloro- N- of 5- (2- isopropoxy -5- methyl -4- (piperidin-4-yl phenyl)-N-2- (isopropelsulfonyl) benzene
Base) -2,4- diamine dihydrochlorides (6.31g) add 50mL there-necked flasks in.Add 19g aqueous acetone solutions (3:1, v/v).Stirring adds
Heat is added dropwise the NaOH aqueous solution of 10g about 10% to 55 degree.Room temperature is cooled to after completion of dropping, is diluted with 42g purified waters, continued
Stirring 1 hour.Filtering, collects filter cake.Filter cake is vacuum dried, and obtains the chloro- N- of 5- (2- isopropoxy -5- methyl -4- (piperidin-4-yls
Phenyl)-N-2- (isopropelsulfonyl) phenyl) -2,4- diamines.Purity is not less than 99%, and single contaminant is not higher than 0.1%.
MS(ESI+):558.1(M+1)+。1H NMR(DMSO-d6):δ8.44(d,3.4,1H),8.20(s,1H),8.02
(s,1H),7.80-7.82(m,1H),7.56-7.60(m,1H),7.49(s,1H),7.30-7.33(m,1H),6.80(s,1H),
4.49-4.54(m,1H),3.42-3.47(m,1H),3.02(d,4.8,2H),2.57-2.72(m,3H),2.10(m,3H),
1.47-1.60(m,4H),1.21(d,2.4,6H),1.14(d,2.6,6H)。
Claims (12)
1. the midbody compound for preparing Ceritinib shown in formula (1)：
Wherein, R be substituted or unsubstituted aromatic ring methylene, heteroaromatic methylene, wherein, the aromatic ring be C6-C10Aromatic ring, institute
It is that the substitution base is hydroxyl, halogen containing selected from least one of N, S or O heteroatomic 5 to 8 yuan of heteroaromatics to state heteroaromatic
Element, amino, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl group, C1-C6Alkyl-carbonyl, C1-C6Alkylamine
Base, C1-C4One or more in alkyl-carbonyl；X is halogen.
2. the midbody compound and its chemically acceptable salt for preparing Ceritinib shown in formula (2)：
Wherein, R is substituted or unsubstituted aromatic ring methylene, heteroaromatic methylene；Wherein, the aromatic ring is C6-C10Aromatic ring, institute
It is that the substitution base is hydroxyl, halogen containing selected from least one of N, S or O heteroatomic 5 to 8 yuan of heteroaromatics to state heteroaromatic
Element, amino, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl group, C1-C6Alkyl-carbonyl, C1-C6Alkylamine
Base, C1-C4One or more in alkyl-carbonyl.
3. the intermediate compound for preparing Ceritinib as shown in formula (1) or formula (2) according to claim 1 and 2
Thing, wherein, R be unsubstituted benzyl or the substituted base of phenyl ring upper band benzyl or unsubstituted menaphthyl or
The menaphthyl of the substituted base of naphthalene nucleus upper band；Wherein, the definition of substitution base is identical with claim 1 or 2.
4. the midbody compound for preparing Ceritinib shown in formula (1)：
Wherein, R is the benzhydryl of unsubstituted benzhydryl or the substituted base of phenyl ring upper band, the substitution base be hydroxyl,
Halogen, amino, C1‐C6Alkyl, C3‐C6Cycloalkyl, C2‐C6Alkenyl, C2‐C6Alkynyl group, C1‐C6Alkyl-carbonyl, C1‐C6Alkylamine
Base, C1‐C4One or more in alkyl-carbonyl；X is halogen.
5. the midbody compound and its chemically acceptable salt for preparing Ceritinib shown in formula (2)：
Wherein, R is the benzhydryl of unsubstituted benzhydryl or the substituted base of phenyl ring upper band, the substitution base be hydroxyl,
Halogen, amino, C1‐C6Alkyl, C3‐C6Cycloalkyl, C2‐C6Alkenyl, C2‐C6Alkynyl group, C1‐C6Alkyl-carbonyl, C1‐C6Alkylamine
Base, C1‐C4One or more in alkyl-carbonyl.
6. compound and its chemically acceptable salt according to claim 2 or 5, wherein, described its can chemically connect
The salt received is chemically acceptable acylate or inorganic acid salt, and the inorganic acid salt is hydrochloride, hydrobromate, hydroiodic acid
Salt, sulfate or disulfate, phosphate or hydrophosphate or dihydric phosphate；Acylate is formates, acetate, propionic acid
Salt, butyrate, oxalates, fumarate, maleate, succinate, tartrate, mandelate, methane sulfonates, benzene sulphur
Hydrochlorate, tosilate or camsilate.
7. a kind of method by the prepare compound 4 of compound 3 shown in following response path：
Wherein, the definition of R and X is identical with described in claim 1；
The step of by 3 prepare compound 1 of compound, be corresponding with the halide reaction generation of corresponding benzyl position using compound 3
Quarternary ammonium salt compound 1；Wherein, benzyl position halide is the benzyl position halide of substituted or unsubstituted aromatic ring or heteroaromatic, its
In, the aromatic ring is C6-C10Aromatic ring, the heteroaromatic is containing selected from heteroatomic 5 to the 8 yuan of virtues of at least one of N, S or O
Heterocycle, the substitution base is hydroxyl, halogen, amino, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl group,
C1-C6Alkoxy, C1-C6Alkyl-carbonyl, C1-C6Alkyl amine group, C1-C4One or more in alkyl-carbonyl；
It is as catalyst, and alcohol using boron hydride or its composition by the reduction step of compound 1 to compound 2
Class solvent carries out the reduction of pyridinium salt；
Benzyl protecting group is removed by using catalytic hydrogenation or transfer hydrogenation process by compound 2, is generated auspicious for preparing color
For the midbody compound 4 of Buddhist nun；Wherein, catalyst used is palladium carbon, ruthenium carbon, rhodium carbon or platinum carbon, and hydrogen source used is hydrogen
Or using ammonium formate, formic acid transfer hydrogenation,
Wherein, the reaction temperature of the catalytic hydrogenation is 90 DEG C, and reaction pressure is 1MPa.
8. method according to claim 7, wherein, the step of by 3 prepare compound 1 of compound in, the benzyl position halogenation
Thing is benzyl chloride, bromobenzyl, a fluorobenzyl chloride, iodine benzyl, 2- chloromethyl naphthalenes, 2- bromomethyls naphthalene, 1 chloromethyl naphthalene or 1- bromomethyl naphthalenes.
9. method according to claim 7, wherein, in the reduction step by compound 1 to compound 2, the boron hydrogen
Compound is sodium borohydride, potassium borohydride, lithium borohydride or zinc borohydride；Reaction temperature is -20 DEG C to 60 DEG C.
10. method according to claim 7, wherein, alcohols solvent is C1~C6Alcohol, or its composition.
11. methods according to claim 10, wherein, the alcohols solvent is methyl alcohol, ethanol, propyl alcohol, isopropanol, fourth
Alcohol, isobutanol, amylalcohol, 2- amylalcohols or hexanol, or its composition.
Application of 12. compounds according to claim 1 and 2 in Ceritinib is prepared.
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| CN105777617B (en) * | 2014-12-26 | 2018-11-06 | 上海医药工业研究院 | Synthetic intermediate of Ceritinib and preparation method thereof |
| CN104803908A (en) * | 2015-03-26 | 2015-07-29 | 药源药物化学（上海）有限公司 | Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride as well as preparation method and application of hydrate |
| WO2016199020A1 (en) * | 2015-06-08 | 2016-12-15 | Dr. Reddy's Laboratories Limited | Process for preparation of ceritinib |
| CN106565593B (en) * | 2015-10-10 | 2019-03-01 | 常州市勇毅生物药业有限公司 | A kind of preparation method of Ceritinib intermediate |
| CN105646452B (en) * | 2015-12-24 | 2018-05-01 | 北京康立生医药技术开发有限公司 | A kind of synthetic method of kinases inhibitor |
| CN106083595A (en) * | 2016-06-08 | 2016-11-09 | 常州安迪沃克医药科技有限公司 | The synthetic method of cancer therapy drug Ceritinib intermediate 2 chlorine (bromine) 4 fluorine 5 Methylnitrobenzene |
| CN106674084B (en) * | 2016-12-20 | 2019-03-01 | 山东轩德医药科技有限公司 | A kind of preparation method of 2- isopropyl oxygroup -5- methyl -4- (piperidin-4-yl) aniline dihydrochloride |
| CN111410649B (en) * | 2019-01-04 | 2022-09-02 | 南京海润医药有限公司 | Preparation method of ceritinib |
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