CN104892526A - Preparation method of 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine - Google Patents
Preparation method of 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine Download PDFInfo
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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- 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 relates to a novel preparation method of 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine. According to the method, o-aminothiophenol is taken as the starting raw material, and 2,5-dichloro-N-(2-isopropylsulfonyl) phenyl) pyrimidine-4-amine is obtained after 5 steps including alkylation, acylation, oxidation, hydrolysis and coupling. Compared with the conventional processes, the process does not use a stinking isopropyl mercaptan reagent and is more environment-friendly. Raw materials for the whole synthesis route are easy to get, the operation of a reaction unit is simple and convenient, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of 2,5-bis-chloro-N-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, and for the look auspicious preparation for Buddhist nun.
Background technology
Lung cancer is the malignant tumour that global incidence is the highest, and due to various factors impacts such as environment, increases with the speed per year over 3%.And have in the patient made a definite diagnosis 80-85% for nonsmall-cell lung cancer (NSCLC), wherein 2%-7% case driven by the rearrangement (rearrangement) of Nucleophosmin-anaplastic lymphoma kinase (ALK), cause the accelerating growth of cancer cells, sb.'s illness took a turn for the worse.Look auspicious is a kind of oral, selectivity ALK inhibitor for Buddhist nun, achieves breakthrough in clinical study in treatment Metastatic Nsclc (NSCLC) patient.Have approved food and medicine Surveillance Authority of the U.S. on April 29 in 2014 (FDA) look auspicious for Buddhist nun for after Xalkori (crizotinib) treatment, sb.'s illness took a turn for the worse or treatment to the Nucleophosmin-anaplastic lymphoma kinase positive (ALK+) Metastatic Nsclc (NSCLC) patient that Xalkori does not tolerate.
Current published document [J.Med.Chem.2013,56,5675-5690] look auspicious is as follows for Buddhist nun (LDK378) preparation method:
The synthesis of key intermediate compound 7 (the chloro-N-of 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine) is a very important synthesis step.According to document (WO2008073687) and achievement after deliberation, find when from midbody compound 5 and 6 synthetic intermediate compound 7, need to use excessive sodium hydrogen to react in DMSO and DMF mixed solvent, sodium hydrogen is inflammable and explosive, dangerous high in production operation, and this reaction conversion ratio can reach 60%, but because midbody compound 7 easily decomposes under strongly alkaline conditions, under small-scale (below 10g), yield can reach about 45%, and yield and declining to a great extent after exceeding 1Kg, lower than 30%, solvent DMSO in last handling process, DMF and excessive intermediate 6 are difficult to eccysis, aftertreatment is complicated, also very big pollution can be produced.In addition, it is auspicious for Buddhist nun's preparation that the midbody compound 7 obtained needs could to be used for look through column chromatography purification, purge process loss more than 30%, make this route overall yield low (calculating still lower than 20% from compound 5), cost is high, operational hazards, is not suitable for suitability for industrialized production.And because the look auspicious market requirement for Buddhist nun is very large, preparation consumption is also very large simultaneously, will be therefore very huge to the demand of bulk drug, this just brings extreme difficulties to suitability for industrialized production.
The route of synthesis being found intermediate 5 by literature query is (WO2011140338):
But the adjacent fluoronitrobenzene of starting raw material is expensive, and isopropyl mercaptan is then the reagent of extremely stench, and close to the highest ranking 5 grades (hydrogen sulfide is 4.5 grades) of odor strength, suction can cause anosmia.Substantially cannot use on a large scale because serious environment event can be caused aborning.Simultaneously due to the impact of element sulphur in isopropyl mercaptan, palladium can be caused poisoning in the hydrogenation of follow-up palladium carbon catalysis, causing the catalyzer that needs are more---weight percent is up to 10%, and need to add in batches, not only cause production cost expensive, and add palladium carbon cause serious potential safety hazard because constantly drive still in hydrogenation process.
Scholar is had to propose to use the less near amino thiophenols of stink for when starting raw material prepares compound 2 (J.Med.Chem.2002,45,2229-2239) in research afterwards.
But still to use highly basic potassium tert.-butoxide in this reaction, react in dehydrated alcohol, expend more solvent.And in subsequent steps, how oxygenated compound 2 to target compound (compound 5) does not then have bibliographical information.If the method being sulfone according to general sulfide oxidation uses hydrogen peroxide or Peracetic Acid to be oxidized, because amino is also easy to oxidized, reacting very assorted does not have product substantially.
And after acyl group protection is carried out to compound 2; re-use hydrogen peroxide or Peracetic Acid is oxidized; after thioether generation sulfone; there is very strong electron-withdrawing power; the amine protecting group at ortho position is caused to be easy to dissociate; amine after deprotection is then very easy to oxidized, so use conventional oxygenant to carry out reacting reaction still can be caused still very assorted, does not substantially expect product.
Even if use very uneconomical and be not suitable for industrialized method and obtain compound 5, according to existing method, sodium hydrogen or stronger alkali must be used to carry out the coupling of compound 5 and compound 6.And when using highly basic, whole reaction system can blackening, produce tarry matters, making reaction yield, very low (reaction yield of more than 1Kg is no more than 30%.WO2011140338 is repeated this experiment, need column chromatography just can obtain product, and yield only has 33%), and be not easy process.The highly basic that can discharge a large amount of hydrogen in the reaction using sodium hydrogen so then can bring very large potential safety hazard aborning.In reaction process, reaction is easy to out of control, releases a large amount of hydrogen and heat, brings great potential safety hazard to production.In follow-up cancellation reaction, also can produce a large amount of hydrogen and heat, there is severe compromise.And aftertreatment produces a large amount of waste residue, waste liquid, and these waste residue and liquids extremely stench, there is very large pungency, even if the contact of trace also can cause serious anaphylaxis, bring great harm to environment.
Therefore a kind of applicable suitability for industrialized production newly must be developed, safety, eco-friendly, easy handling, the technique that cheap but constant product quality is excellent.
Summary of the invention
The object of the present invention is to provide a kind of newly for the preparation of look auspicious intermediate for Buddhist nun and preparation method thereof, this operational path is simple, and raw material is cheap, and safety is easy to get, eco-friendly, easy handling, is applicable to suitability for industrialized production.The midbody compound 7 that this preparation method obtains is cheap but constant product quality is excellent.Total recovery 68%.
The present inventor finds that after constantly attempting the aminothiophenol using basic odorless is starting raw material, reacts, through oxidation after acidylate, can easily obtain midbody compound 5 after last deprotection in alkaline environment with halo isopropyl alkane.Midbody compound 5, under the palladium complex catalyst of catalytic amount, with compound 6 coupling smoothly in the weakly alkaline environments such as carbonate, obtains highly purified midbody compound 7.Avoid hazardous agents such as using sodium hydrogen, the step that when decreasing aftertreatment, shrend is gone out and wash simultaneously, namely obtains purer product after directly steaming desolventizes cold filtration, reduce reaction volume, improve production efficiency, substantially do not have waste liquid to produce, improve environmental friendliness.
The invention provides a kind of 2; the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine; concrete synthetic route (example can make the present invention of those skilled in the art's comprehend, but it does not limit the present invention in any way) as follows:
Wherein,
(a) compound 1 and CH
3cH (CH
3) alkylated reaction occurs X, generates compound 2, wherein, X is halogen Cl, Br, I or methylsulfonyl, trifyl, the benzenesulfonyl of benzenesulfonyl or replacement, described replacement refers to by methyl, ethyl, one or more in sec.-propyl replace, react and carry out under solvent and alkali exist, solvent is water, and alkali is selected from sodium hydroxide or potassium hydroxide or its mixture;
B () compound 2 and acylating reagent generation acylation reaction, generate compound 3, the C1-C6 alkyl of acylating reagent to be acetic anhydride RCOOCOR or acyl chlorides RCOX ', R be straight or branched, and X ' is halogen; Preferably, R is methyl or ethyl;
C () compound 3 and oxygenant generation oxidizing reaction, generate compound 4;
D there is hydrolysis reaction in () compound 4, generates compound 5 in a solvent;
E there is linked reaction in () compound 5 and compound 6, generates compound 7, react and carry out under the existence of palladium catalyst and alkali, alkali is selected from cesium carbonate, salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, a kind of or wherein multiple mixture in sodium tert-butoxide.
Further, in described step (a), X is Cl, Br or I.Consider raw materials cost and reactive behavior, yield, and product purity, the step more optimized, X is Br; Temperature of reaction is 20-100 DEG C; Further optimize temperature of reaction can control at 40-50 DEG C; Solvent is water; When alkali is sodium hydroxide, reaction very well, and do not expend solvent.
The reaction of step (b) can be carried out in the presence of solvent, and solvent is acetic acid or methylene dichloride;
Further, in described step (b), acylating reagent is acid anhydrides or acyl chlorides; Optimize a step, considering cost and reactive behavior, yield and product purity, acylating reagent elects acetic anhydride or Acetyl Chloride 98Min. as; When acylating reagent is acetic anhydride, solvent is acetic acid, and temperature of reaction is 20-100 DEG C.When acylating reagent is Acetyl Chloride 98Min., solvent can elect methylene dichloride as, and acylation reaction can be carried out in the presence of a base, and alkali is selected from triethylamine, pyridine or diisopropyl ethyl amine; Consider environmental protection, smell, and cost, alkali is preferably triethylamine.Temperature of reaction controls at-20 to 50 DEG C.Further consider that the cost acylating reagent of integrated artistic is acetic anhydride, solvent is acetic acid, and temperature of reaction is 20-100 DEG C, and reaction system is directly used in next step without processing further.Corresponding carboxylic acid can certainly be adopted under the effect of DCC or EDC condensing agent, to carry out condensation reaction to amino and to generate corresponding acid amides.
Further, in described step (c), oxygenant is selected from Sodium peroxoborate, four hydrated sodium perborates, potassium per(oxy)borate, Peracetic Acid, benzoyl hydroperoxide, metachloroperbenzoic acid or hydrogen peroxide.Reaction can be carried out in the presence of solvent, and solvent is selected from toluene, tetrahydrofuran (THF), acetic acid, water or lower alcohol.More optimize a step, considering cost, environment protection, operability and industrialization adaptability, oxygenant is four hydrated sodium perborates or Sodium peroxoborate.Solvent is acetic acid; Temperature of reaction is 20-100 DEG C.Use this condition, step (b) and step (c) can separate operations, also the reaction of step (b) can be directly used in step (c) without aftertreatment, and aftertreatment in step (c) is also convenient.
Further, in described step (d), react and carry out under alkali and solvent exist.More optimize a step, considering cost, reactive behavior, operability and industrialization adaptability, alkali can be selected from one or more the mixture in sodium hydroxide, potassium hydroxide, sodium methylate, potassium methylate, sodium carbonate, salt of wormwood, cesium carbonate or potassium tert.-butoxide.More optimizing a step alkali is sodium hydroxide, potassium hydroxide or both mixtures; Solvent is selected from one or more the mixed solvent in water, methyl alcohol, ethanol, Virahol.Further optimizing alkali is sodium hydroxide, and solvent is the mixed solvent of water and ethanol; Temperature of reaction is 40-100 DEG C.Further optimize the mixed solvent that solvent is the mass ratio 0.1 to 10 of water and ethanol.
Further in described step (e), more optimize the mixture that a step palladium catalyst is selected from palladium, palladium salt or one or more and part in them, in reaction system, generate catalyzer (complex compound of palladium or palladium salt and part), or use the shaping palladium catalyst of palladium and the part can bought on the market.Further optimize, considering cost, reactive behavior, operability and industrialization adaptability, palladium catalyst is the complex compound of palladium salt and part, and described palladium salt is selected from palladium, Palladous chloride etc.; Described part is selected from two (diphenylphosphine) ferrocene of triphenylphosphine, xantphos, X-Phos or 1,1'-.Further optimizing palladium salt is palladium; Part is two (diphenylphosphine) ferrocene of triphenylphosphine xantphos, X-Phos or 1,1'-.Shaping palladium catalyst comprises two (diphenylphosphine) ferrocene Palladous chlorides of tetrakis triphenylphosphine palladium, two (triphenylphosphine) palladium chloride, triphenylphosphine palladium acetate or 1,1'-etc., but is not limited thereto.In reaction, alkali is preferably cesium carbonate or salt of wormwood; Reaction is preferably carried out in the presence of solvent, and solvent is toluene; Temperature of reaction is 70-130 DEG C.
The compound of general formula (3) and the compound of general formula (4) is disclosed in the present invention; they are important intermediate of the chloro-N-of preparation 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (compound 7):
Wherein, R is the C1-C6 alkyl of straight or branched, and preferably, R is methyl or ethyl.
Compound 7 can be used for the compound coupling protected with the hydrochloride of piperidine intermediate (compound 8) or its hydrate or Boc, obtains look auspicious for Buddhist nun (Ceritinib, or LDK-378).
The structural formula of compound 8 is:
General scheme is as follows:
Use near amino thiophenols provided by the invention is starting raw material, through alkylation, and acidylate, oxidation, the route of hydrolysis and palladium chtalyst coupling; In environment protection, avoid the isopropyl mercaptan employing extremely stench, and the aftertreatment of each step is all very simple, does not substantially have the liquid and waste slag produced generation of high pollution; In industrial Applicability and security, avoid and use dangerous sodium hydrogen.
The present invention significantly reduces the poisonous and hazardous waste liquid of the risk of aftertreatment and a large amount of of generation thus, significantly improve the security and environment friendly of producing key intermediate compound 7, significantly reduce production cost, substantially increase industrial security, operability and feasibility, thus provide a kind of new method for significantly reducing the product look auspicious cost for Buddhist nun.In addition, compound 7 purity that this route obtains is high, and what steady quality finally can be stable prepare, and highly purified look auspicious is for Buddhist nun.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment one 2-(sec.-propyl sulfydryl) aniline
By near amino thiophenols (99.00g), water (300mL) adds in reaction flask, stirs.The NaOH aqueous solution.Drip 2-N-PROPYLE BROMIDE 116.85g.Dropwise and be warming up to 40-50 DEG C of reaction 2 hours.Cool after completion of the reaction, add extraction into ethyl acetate twice.Merge organic phase, washing once.Steaming desolventizes, and obtains 2-(sec.-propyl sulfydryl) aniline 125.6g.Yield 95%.
MS(ESI+):168.1(M+1)+。
Embodiment two N-(2-(isopropylthio) phenyl) ethanamide
By 2-(sec.-propyl sulfydryl) aniline (132g), acetic acid (132mL) joins in reaction flask.Stir, be warming up to 40 DEG C.Drip acetic anhydride (96.80g).Dropwise rear stirring 30 minutes.After completion of the reaction, pour in frozen water, extraction into ethyl acetate twice.Merge organic phase, washing once.Steaming desolventizes, and obtains N-(2-(isopropylthio) phenyl) ethanamide 161.9g.Yield 98%.
MS(ESI+):210.1(M+1)+。1H NMR(CDCl3):δ8.40(d,4.0,1H),7.47-7.49(m,1H),7.30-7.34(m,1H),7.00-7.04(m,1H),3.09-3.14(m,1H),2.21(s,3H),1.28-1.32(d,2.6,6H)。
Embodiment three N-(2-(isopropelsulfonyl) phenyl) ethanamide
By N-(2-(isopropylthio) phenyl) ethanamide (165g), acetic acid (330mL) joins in reaction flask.Stir, be warming up to 40 DEG C.Add four hydrated sodium perborates (364g) in batches.Add rear continuation to stir 2 hours at 40 DEG C.Be warming up to 50-60 DEG C and continue reaction until react complete.Be cooled to 20-30 DEG C.Join in frozen water.Suction filtration, filter cake washes twice with water.Collect filter cake.After drying, obtain Tan solid N-(2-(isopropelsulfonyl) phenyl) ethanamide 173g.Yield 91%
MS(ESI+):242.1(M+1)+。1H NMR(CDCl3):δ8.46-8.50(m,1H),7.79-7.83(m,1H),7.59-7.65(m,1H),7.20-7.25(m,1H),3.16-3.22(m,1H),1.28-1.32(m,6H)。
Embodiment four N-(2-(isopropelsulfonyl) phenyl) ethanamide
By 2-(sec.-propyl sulfydryl) aniline (167g), methylene dichloride (1670mL) joins in reaction flask.Stir, add metachloroperbenzoic acid (518g) in batches.Add rear continuation reaction until react complete.Add frozen water, separatory, collect organic phase.Once, once, once, evaporate to dryness obtains Tan solid N-(2-(isopropelsulfonyl) phenyl) ethanamide 185g in washing in sodium bicarbonate aqueous solution washing in washing.Yield 96%.
MS(ESI+):242.1(M+1)+。1H NMR(CDCl3):δ8.46-8.50(m,1H),7.79-7.83(m,1H),7.59-7.65(m,1H),7.20-7.25(m,1H),3.16-3.22(m,1H),2.20-2.22(m，3H),1.28-1.32(m,6H)。
Embodiment five N-(2-(isopropelsulfonyl) phenyl) ethanamide
By 2-(sec.-propyl sulfydryl) aniline (132g), acetic acid (132mL) joins in reaction flask.Stir, be warming up to 40 DEG C.Drip acetic anhydride (96.80g).Dropwise rear stirring 30 minutes.Add four hydrated sodium perborates (364g) in batches.Add rear continuation to stir 2 hours at 40 DEG C.Be warming up to 50-60 DEG C and continue reaction until react complete.Be cooled to 20-30 DEG C.Join in frozen water 800g.Suction filtration, filter cake washes twice with water.Collect filter cake.After drying, obtain Tan solid N-(2-(isopropelsulfonyl) phenyl) ethanamide 170g.Yield 89%.
MS(ESI+):242.1(M+1)+。1H NMR(CDCl3):δ8.46-8.50(m,1H),7.79-7.83(m,1H),7.59-7.65(m,1H),7.20-7.25(m,1H),3.16-3.22(m,1H),2.20-2.22(m，3H),1.28-1.32(m,6H)。
Embodiment six 2-(isopropelsulfonyl) aniline
By N-(2-(isopropelsulfonyl) phenyl) ethanamide (120.00g), 95% ethanol 60mL joins in 1L three-necked bottle.Add NaOH solution.Be warming up to 70 DEG C, be stirred to and react completely.Add 240mL frozen water, be cooled to less than 10 DEG C.Filter, filter cake washes with water, collects filter cake.Drying, obtains Tan solid 2-(isopropelsulfonyl) aniline 94g.Yield 95%.
MS(ESI+):200.1(M+1)+。1H NMR(CDCl3):δ7.60-7.65(m,1H),7.31-7.35(m,1H),6.76-6.79(m,1H),6.72(d,4.0,1H),3.30-3.45(m,1H),1.27-1.31(m,6H)。
The chloro-N-of embodiment 72,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine
By 2-(isopropelsulfonyl) aniline (100g); 2; 4; 5-trichloropyrimidine (125g), palladium (2.2g), triphenylphosphine (6.7g); cesium carbonate (200g); toluene (1L) joins in reaction flask, nitrogen protection, is warming up to backflow until react complete.Be cooled to less than 50 DEG C, add ethyl acetate (500mL), filter, collect filtrate.Add methyl tertiary butyl ether crystallization after filtrate is concentrated to filter, collect filter cake.The chloro-N-of faint yellow solid 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine 148g is obtained after drying.Yield 85%.
MS(ESI+):346.1(M+1)+。1H NMR(CDCl3):δ9.61(s,1H),8.16-8.19(d,4.4,1H),7.84-7.85(d,0.8,1H),7.45-7.48(m,1H),7.26-7.30(m,1H)6.85-6.89(m,1H),2.74-2.78(m,1H),0.85-0.88(d,3.4,6H)。
The chloro-N-of embodiment 82,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine
By 2-(isopropelsulfonyl) aniline (100g); 2; 4; 5-trichloropyrimidine (138g), palladium (0.25g), Xantphos (1.27g); salt of wormwood (300g); toluene (2L) joins in reaction flask, nitrogen protection, is warming up to backflow until react complete.Be cooled to less than 50 DEG C, add ethyl acetate (1000mL), filter, collect filtrate.Add methyl tertiary butyl ether crystallization after filtrate is concentrated to filter, collect filter cake.The chloro-N-of faint yellow solid 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine 148g is obtained after drying.Yield 90%.
MS(ESI+):346.1(M+1)+。1H NMR(CDCl3):δ9.61(s,1H),8.16-8.19(d,4.4,1H),7.84-7.85(d,0.8,1H),7.45-7.48(m,1H),7.26-7.30(m,1H)6.85-6.89(m,1H),2.74-2.78(m,1H),0.85-0.88(d,3.4,6H)。
The chloro-N-of embodiment 92,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine
By 2-(isopropelsulfonyl) aniline (100g); 2; 4; 5-trichloropyrimidine (138g), [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (1.0g); salt of wormwood (300g); toluene (2L) joins in reaction flask, nitrogen protection, is warming up to backflow until react complete.Be cooled to less than 50 DEG C, add ethyl acetate (1000mL), filter, collect filtrate.Add methyl tertiary butyl ether crystallization after filtrate is concentrated to filter, collect filter cake.The chloro-N-of faint yellow solid 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine 148g is obtained after drying.Yield 88%.
MS(ESI+):346.1(M+1)+。1H NMR(CDCl3):δ9.61(s,1H),8.16-8.19(d,4.4,1H),7.84-7.85(d,0.8,1H),7.45-7.48(m,1H),7.26-7.30(m,1H)6.85-6.89(m,1H),2.74-2.78(m,1H),0.85-0.88(d,3.4,6H)。
The preparation of the chloro-N-of embodiment ten 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl phenyl)-N-2-(isopropelsulfonyl) phenyl)-2,4-diamine dihydrochloride
By 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride (17.00g) and 2; the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (18.32g) adds in 500mL there-necked flask, adds Virahol 170mL.Stirring heating back flow reaction is spent the night.Filter after being cooled to room temperature, wash, collect filter cake.Filtration cakes torrefaction obtains the chloro-N-of faint yellow solid 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl phenyl)-N-2-(isopropelsulfonyl) phenyl)-2,4-diamine dihydrochloride 30.4g.Yield 91%.
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 preparation of the chloro-N-of embodiment 11 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl phenyl)-N-2-(isopropelsulfonyl) phenyl)-2,4-diamines (LDK-378)
Chloro-for 5-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl phenyl)-N-2-(isopropelsulfonyl) phenyl)-2,4-diamine dihydrochloride (6.31g) are added in 50mL there-necked flask.Add 19g aqueous acetone solution (3:1, v/v).Be heated with stirring to 55 DEG C, drip the NaOH aqueous solution of 10g about 10%.Be cooled to room temperature after dropwising, with the dilution of 42g purified water, continue stirring 1 hour.Filter, collect filter cake.Filter cake vacuum-drying, obtains the chloro-N-of off-white color solid 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl phenyl)-N-2-(isopropelsulfonyl) phenyl)-2,4-diamines 5.19g.Yield 93%.
MS(ESI+):558.1(M+1)+。1HNMR(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)。
Comparative example repeats document [J.Med.Chem.2013,56,5675-5690], adopts NaH to prepare the chloro-N-of 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine
In the suspension of the NaH (28.85g) that the solution of less than the 0 DEG C DMF/DMSO by 2-(isopropelsulfonyl) aniline (100g) (400mL, volume ratio is 9/1) drops to stirring in DMF/DMSO mixture (1000mL/100mL).0 DEG C is stirred 30 minutes, drips and is diluted in 400mLDMF/DMSO (volume ratio: 2,4,5-trichloropyrimidines (162g, 2eq) 9/1).By solution temperature to room temperature, stirring is spent the night.Reaction solution is slowly poured in frozen water, is extracted with ethyl acetate three times, merge organic phase.Anhydrous sodium sulfate drying, filters, and collect filtrate, filter cake ethyl acetate is washed.Merging filtrate, is concentrated into dry.Column chromatography (silica gel dress post, the heptane drip washing with containing ethyl acetate (volume ratio: 1% to 20%)), obtains the chloro-N-of faint yellow solid 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine 43g.Yield 24.7%.
MS(ESI+):346.1(M+1)+。1H NMR(CDCl3):δ9.61(s,1H),8.16-8.19(d,4.4,1H),7.84-7.85(d,0.8,1H),7.45-7.48(m,1H),7.26-7.30(m,1H)6.85-6.89(m,1H),2.74-2.78(m,1H),0.85-0.88(d,3.4,6H)。
Claims (22)
1. the preparation method of bis-chloro-N-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, its synthetic route is as follows:
Wherein,
(a) compound 1 and CH
3cH (CH
3) alkylated reaction occurs X, generates compound 2; Wherein, X is halogen or sulphonate leaving group, such as Cl, Br, I, methylsulfonyl, trifyl, the benzenesulfonyl of benzenesulfonyl or replacement, described replacement refers to by methyl, ethyl, one or more in sec.-propyl replace, react and carry out under solvent and alkali exist, solvent is water, and alkali is selected from sodium hydroxide or potassium hydroxide or its mixture;
B () compound 2 and acylating reagent generation acylation reaction, generate compound 3, the C1-C6 alkyl of acylating reagent to be acetic anhydride RCOOCOR or acyl chlorides RCOX ', R be straight or branched, and X ' is halogen;
C () compound 3 and oxygenant generation oxidizing reaction, generate compound 4;
D there is hydrolysis reaction in () compound 4, generates compound 5 in a solvent;
E there is linked reaction in () compound 5 and compound 6, generates compound 7, react and carry out under the existence of palladium catalyst and alkali, alkali is selected from cesium carbonate, salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, a kind of or wherein multiple mixture in sodium tert-butoxide.
2. the preparation method of 2,5-bis-chloro-N-according to claim 1 (2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (a), X is Cl, Br or I.
3. the preparation method of 2,5-bis-chloro-N-according to claim 1 (2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (a), temperature of reaction is 20-100 DEG C.
4. the preparation method of 2,5-bis-chloro-N-according to claim 1 (2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (a), temperature of reaction is 40-50 DEG C; Solvent is water; Alkali is sodium hydroxide.
5. the preparation method of 2,5-bis-chloro-N-according to claim 1 (2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (b), acylating reagent is acetic anhydride or Acetyl Chloride 98Min.; The reaction of step (b) can be carried out in the presence of solvent, and solvent is acetic acid or methylene dichloride.
6. the preparation method of 2,5-bis-chloro-N-according to claim 5 (2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (b), acylating reagent is acetic anhydride; Solvent-free reaction, or solvent is acetic acid; Temperature of reaction is 20-100 DEG C.
7. according to claim 62; the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine; it is characterized in that: in described step (b), reaction system is directly used in next step without further aftertreatment.
8. the preparation method of 2,5-bis-chloro-N-according to claim 5 (2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (b), acylating reagent is Acetyl Chloride 98Min.; Solvent is methylene dichloride; Temperature of reaction is-20-50 DEG C; Reaction is carried out in the presence of a base, and alkali is ethamine, pyridine or diisopropyl ethyl amine, is preferably triethylamine.
9. according to claim 12, the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (c), oxygenant is selected from Sodium peroxoborate, four hydrated sodium perborates, potassium per(oxy)borate, benzoyl hydroperoxide, metachloroperbenzoic acid or hydrogen peroxide; Reaction is carried out in the presence of solvent, and solvent is selected from toluene, tetrahydrofuran (THF), acetic acid, water or lower alcohol.
10. according to claim 92, the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (c), oxygenant is four hydrated sodium perborates or Sodium peroxoborate; Solvent is acetic acid; Temperature of reaction is 20-100 DEG C.
11. according to claim 12; the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine; it is characterized in that: in described step (d); reaction is carried out in the presence of a base, and alkali is selected from one or more the mixture in sodium hydroxide, potassium hydroxide, sodium methylate, potassium methylate, sodium carbonate, salt of wormwood, cesium carbonate or potassium tert.-butoxide.
12. according to claim 11 2, the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (d), alkali is selected from sodium hydroxide, potassium hydroxide or both mixtures; Solvent is one or more the mixed solvent in water, methyl alcohol, ethanol, Virahol.
The preparation method of 13. 2,5-bis-chloro-N-according to claim 12 (2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (d), alkali is sodium hydroxide; Solvent is the mixed solvent of water and ethanol; Temperature of reaction is 40-100 DEG C.
14. according to claim 13 2; the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine; it is characterized in that: in described step (d), solvent be water and ethanol mass ratio be the mixed solvent of 0.1 to 10.
15. according to claim 12; the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine; it is characterized in that: in described step (e); palladium catalyst is selected from the mixture of palladium, palladium salt or one or more and part in them; in reaction system, generate the complex compound of palladium or palladium salt and part, or palladium catalyst is the shaping palladium catalyst of commercially available palladium and part.
16. according to claim 15 2, the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (e), palladium catalyst is the complex compound of palladium salt and part, and described palladium salt is selected from palladium or Palladous chloride; Described part is selected from two (diphenylphosphine) ferrocene of triphenylphosphine, xantphos, X-Phos or 1,1'-.
The preparation method of 17. 2,5-bis-chloro-N-according to claim 16 (2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (e), palladium salt is palladium; Part is two (diphenylphosphine) ferrocene of triphenylphosphine, xantphos, X-Phos or 1,1'-; Alkali is cesium carbonate or salt of wormwood; Reaction is preferably carried out in the presence of solvent, and solvent is toluene; Temperature of reaction is 70-130 DEG C.
18. according to claim 15 2, the preparation method of the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine, it is characterized in that: in described step (e), palladium catalyst is two (diphenylphosphine) ferrocene palladium chloride of tetrakis triphenylphosphine palladium or 1,1'-; Alkali is cesium carbonate or salt of wormwood; Reaction is preferably carried out in the presence of solvent, and solvent is toluene; Temperature of reaction is 70-130 DEG C.
The compound of 19. general formulas (3):
Wherein R is the C1-C6 alkyl of straight or branched.
The compound of 20. general formulas according to claim 19 (3), R is methyl or ethyl.
The compound of 21. general formulas (4):
Wherein R is the C1-C6 alkyl of straight or branched.
The compound of 22. general formulas according to claim 21 (4), R is methyl or ethyl.
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