CN101935317B - Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof - Google Patents
Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof Download PDFInfo
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Abstract
The invention relates to an synthesizing method of 2-methyl-7-( substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and an intermediate thereof, mainly solving the technical problems of overlength single-line synthetic route, difficult separation and purification, low productivity, high synthesizing cost, narrow applicability, and the like of the traditional synthesizing method. The process method comprises the following steps of: carrying out substitution reaction on 2,4,5-trichloropyrimidine as a raw material and sodium methyl mercaptide to generate the intermediate, i.e. 2,5-dichloro-4-methylthiopyrimidine; then carrying out the substitution reaction with aromatic amine to generate the intermediate, i.e. 2-aromatic amino-4-methylthio-5-chloropyrimidine; then hydrolyzing the methylthio to generate the intermediate, i.e. 2-aromatic amino-4-hydroxy-5-chloropyrimidine; enabling a hydroxyl compound to generate dichloride under the action of phosphorus oxychloride; and finally carrying out the substitution reaction with amine to obtain the 2-methyl-7-(5-chlorine-2-aromatic amido-pyrimidine-4-amino)-4-(4-(4-methyl piperazine-1-base) piperidine-1-base) isoindoline-1-ketone under the action of hydrogen chloride ethyl acetate.
Description
Technical field:
The present invention relates to the synthetic method of a class important drugs molecule 2-methyl-7-(substituted pyrimidines-4-amino)-4-(substituted piperidine-1-yl) 1-isoindolinone and intermediate, be 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone and intermediate 2-aromatic amino-4, the synthetic method of 5-dichloro pyrimidine.
Background technology:
2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone is the important drug molecule of a class, it is as focal adhesion kinase (focal adhesion kinase, FAK) inhibitor, therefore the symptom that can be used as the pharmacological agent signal cascade obstacle (malfunction of signal cascades) relevant with focal adhesion kinase and produce has anti-tumor bioactivity.The synthetic route of having only one piece of PCT patent application (WO 2006/021457) report related compound at present.But we find in experimentation, compound 7 and the 1 reaction conditions (K at report
2CO
3/ DMSO/60 ℃) reaction down, product is very complicated, can not obtain target compound.Even by changing reaction times, temperature of reaction, feed ratio, optimal conditions such as order of addition(of ingredients), the still very difficult target compound of taking.
The synthetic route of such compound of WO 2006/021457 report is as follows:
We have found a method for preparing compound 9 also by groping reaction conditions simultaneously, and are as follows:
But this method isolated yield is not high, has only about 20%.And because this method need be used microwave heating, make the scale that feeds intake each time be restricted, therefore be not suitable for mass preparation.
Summary of the invention:
The object of the present invention is to provide the new synthetic method of a kind of important drugs molecule 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone, mainly solve the separation and purification difficulty that existing synthetic method single line synthetic route is long and exist, productive rate is low, synthetic cost height, technical problem such as suitability is wideless.We search out a class important drugs molecule 2-aromatic amino-4 in experiment, the preparation method of 5-dichloro pyrimidine and use it for synthetic 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone.
Technical scheme of the present invention: the synthetic method of 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone, may further comprise the steps: with 2,4,5-trichloropyrimidine 1 is raw material, by generating intermediate 2 with sodium methyl mercaptide generation substitution reaction, 5-two chloro-4-methylthiopyrimidines 2 take place to generate intermediate 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 after the substitution reaction with aromatic amine 3 then; Intermediate 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 will be generated then after 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 hydrolysis; 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 generates 2-aromatic amino-4,5-dichloro pyrimidine 6 under the phosphorus oxychloride effect; With amine 7 substitution reactions taking place obtains 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 8 at last under the ethyl acetate solution effect of hydrogenchloride.Chemical equation is as follows:
The first step reaction is that 5-trichloropyrimidine 1 is dissolved in organic solvent (as tetrahydrofuran (THF), acetonitrile, Virahol), then the sodium methyl mercaptide aqueous solution slowly is added drop-wise in the reaction solution with 2,4.Dropwise, reaction solution at room temperature stirred 12～24 hours.Obtain pure product 2 after the aftertreatment, 5-two chloro-4-methylthiopyrimidines 2.
The reaction of second step is that 5-two chloro-4-methylthiopyrimidines 2 and aromatic amine 3 are dissolved in propyl carbinol or Virahol with 2, and the ethyl acetate solution with hydrogenchloride slowly is added drop-wise in the reaction solution then.Dropwise, reaction solution is heated to reflux temperature, and stirs 16～24 hours under this temperature.Obtain pure product 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 after the aftertreatment.
Three-step reaction is heated to backflow with reaction solution then for 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 is joined aqueous hydrochloric acid, and reaction solution stirred under this temperature 12～16 hours.Obtain pure product 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 after the aftertreatment.
Four-step reaction is heated to backflow with reaction mixture then for 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 is joined in the phosphorus oxychloride in batches, and reaction solution stirred under this temperature 1～4 hour.Obtain pure product 2-aromatic amino-4 after the aftertreatment, 5-dichloro pyrimidine 6.
The reaction of the 5th step is that 5-dichloro pyrimidine 6 and amine 7 join in propyl carbinol or the aqueous isopropanol, heating for dissolving with 2-aromatic amino-4.Drip the ethyl acetate solution of hydrogenchloride then.Reaction solution is heated to backflow, and stirs 2-4 hour under this temperature.Reaction solution is cooled to 100 ℃ then, adds 2-aromatic amino-4, the ethyl acetate solution of 5-dichloro pyrimidine 6 and hydrogenchloride, this stirs reaction solution 2-4 hour under reflux temperature again.Obtain product 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 8 behind the recrystallization.
The invention has the beneficial effects as follows: the invention provides a kind of 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 8 synthetic routes of novelty, can prepare this class important drugs molecule quickly and easily from raw material cheap, that be easy to get.Compare with the WO 2006/021457 of this compounds of reported first, the present invention not only successful preparation target compound, and aftertreatment is also more easy.Compare with the microwave heating process that we optimized, productive rate has also improved 27%.
Embodiment: following example helps to understand content of the present invention, the present invention includes but is not limited to following related content:
Embodiment
1.2, the synthesis technique one of 5-two chloro-4-methylthiopyrimidines 2
(80g 0.44mol) is dissolved in tetrahydrofuran (THF) (1000mL), and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then with 2,4,5-trichloropyrimidine 1.Dropwise, reaction solution at room temperature stirred 24 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 80g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 93%)
Proton nmr spectra
1H-NMR (DMSO, 400MHz): δ 8.19 (s, 1H), 2.58 (s, 3H); MS (ESI) m/e (M+H
+) 195.
2.2, the synthesis technique two of 5-two chloro-4-methylthiopyrimidines 2
(80g 0.44mol) is dissolved in acetonitrile (1000mL), and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then with 2,4,5-trichloropyrimidine 1.Dropwise, reaction solution at room temperature stirred 24 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 75g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 87%)
3.2, the synthesis technique three of 5-two chloro-4-methylthiopyrimidines 2
(80g 0.44mol) is dissolved in Virahol (1000mL), and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then with 2,4,5-trichloropyrimidine 1.Dropwise, reaction solution at room temperature stirred 24 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 70g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 82%)
4.2, the synthesis technique four of 5-two chloro-4-methylthiopyrimidines 2
(80g 0.44mol) is dissolved in tetrahydrofuran (THF) (1000mL), and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then with 2,4,5-trichloropyrimidine 1.Dropwise, reaction solution at room temperature stirred 12 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 75g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 87%)
5.2, the synthesis technique five of 5-two chloro-4-methylthiopyrimidines 2
(80g 0.44mol) is dissolved in tetrahydrofuran (THF) (1000mL), and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then with 2,4,5-trichloropyrimidine 1.Dropwise, reaction solution at room temperature stirred 18 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 78g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 91%)
The synthesis technique one of (6.2-2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11
With 2,5-, two chloro-4-methylthiopyrimidines 2 (133g, 0.682mol) and ORTHO ANISIDINE (84.5g, 0.687mol) 10 are dissolved in propyl carbinol (2000mL), (4M, 170mL 0.68mol) slowly are added drop-wise in the reaction solution with the ethyl acetate solution of hydrogenchloride then.Dropwise, reaction solution is heated to reflux temperature, and stirs 24 hours under this temperature.Reaction solution is cooled to room temperature, and the solid filtering in the reaction solution falls, and filtrate concentrating done, and the thick product that obtains is put in the saturated sodium bicarbonate aqueous solution of 500mL, the ethyl acetate extraction of mixed solution usefulness 400mL three times.The organic phase anhydrous sodium sulfate drying.Siccative is filtered, and filtrate concentrates the dried pure product 2-of 170g (2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11 (productive rate: proton nmr spectra 88%) that obtains
1H-NMR (DMSO, 400MHz): δ 8.44 (m, 1H), 8.06 (m, 1H), 7.71 (s, 1H), 7.01-6.93 (m, 2H), 6.91-6.90 (m, 1H), 3.93 (s, 3H), 2.61 (s, 3H); MS (ESI) m/e (M+H
+) 282.
The synthesis technique two of (7.2-2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11
With 2,5-, two chloro-4-methylthiopyrimidines 2 (133g, 0.682mol) and ORTHO ANISIDINE (84.5g, 0.687mol) 10 are dissolved in Virahol (2000mL), (4M, 170mL 0.68mol) slowly are added drop-wise in the reaction solution with the ethyl acetate solution of hydrogenchloride then.Dropwise, reaction solution is heated to reflux temperature, and stirs 24 hours under this temperature.Reaction solution is cooled to room temperature, and the solid filtering in the reaction solution falls, and filtrate concentrating done, and the thick product that obtains is put in the saturated sodium bicarbonate aqueous solution of 500mL, the ethyl acetate extraction of mixed solution usefulness 400mL three times.The organic phase anhydrous sodium sulfate drying.Siccative is filtered, and filtrate concentrates the dried pure product 2-of 100g (2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11 (productive rate: 52%) that obtains
The synthesis technique three of (8.2-2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11
With 2,5-, two chloro-4-methylthiopyrimidines 2 (133g, 0.682mol) and ORTHO ANISIDINE (84.5g, 0.687mol) 10 are dissolved in propyl carbinol (2000mL), (4M, 170mL 0.68mol) slowly are added drop-wise in the reaction solution with the ethyl acetate solution of hydrogenchloride then.Dropwise, reaction solution is heated to reflux temperature, and stirs 16 hours under this temperature.Reaction solution is cooled to room temperature, and the solid filtering in the reaction solution falls, and filtrate concentrating done, and the thick product that obtains is put in the saturated sodium bicarbonate aqueous solution of 500mL, the ethyl acetate extraction of mixed solution usefulness 400mL three times.The organic phase anhydrous sodium sulfate drying.Siccative is filtered, and filtrate concentrates the dried pure product 2-of 150g (2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11 (productive rate: 78%) that obtains
The synthesis technique one of (9.2-2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12
(170.0g 0.605mol) joins the aqueous hydrochloric acid (5.0L) of 6M, then reaction solution is heated to backflow, and reaction solution stirred 16 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11.After the reaction solution cooling, concentrate and obtain thick product.Thick product is dissolved in pyridine (200mL), then mixing solutions is poured in the water of 800mL, the solid of generation obtains the pure product 2-of 73g (2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12 (productive rate: 48%) with the ethyl acetate washing back drying of 600mL again
Proton nmr spectra
1H-NMR (DMSO, 400MHz): δ 11.80 (s, 1H), 8.48 (s, 1H), 8.23 (m, 1H), 7.95 (s, 1H), 7.06-7.01 (m, 2H), 6.94-6.90 (m, 1H), 3.87 (s, 3H); MS (ESI) m/e (M+H
+) 252.
The synthesis technique two of (10.2-2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12
(170.0g 0.605mol) joins the aqueous hydrochloric acid (5.0L) of 3M, then reaction solution is heated to backflow, and reaction solution stirred 16 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11.After the reaction solution cooling, concentrate and obtain thick product.Thick product is dissolved in pyridine (200mL), then mixing solutions is poured in the water of 800mL, the solid of generation obtains the pure product 2-of 50g (2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12 (productive rate: 33%) with the ethyl acetate washing back drying of 600mL again
The synthesis technique three of (11.2-2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12
(170.0g 0.605mol) joins the aqueous hydrochloric acid (5.0L) of 6M, then reaction solution is heated to backflow, and reaction solution stirred 12 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11.After the reaction solution cooling, concentrate and obtain thick product.Thick product is dissolved in pyridine (200mL), then mixing solutions is poured in the water of 800mL, the solid of generation obtains the pure product 2-of 70g (2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12 (productive rate: 46%) with the ethyl acetate washing back drying of 600mL again
(12.2-2 '-p-methoxy-phenyl amino)-4, the synthesis technique one of 5-dichloro pyrimidine 13
(23.0g 91.4mmol) joins in the phosphorus oxychloride of 300mL in batches, then reaction mixture is heated to backflow, and reaction solution stirred 1 hour under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12.Excessive phosphorus oxychloride under reduced pressure distilled remove, the crude product that obtains is dissolved in ethyl acetate.Organic phase is used anhydrous sodium sulfate drying after washing with saturated sodium bicarbonate aqueous solution.Remove by filter siccative, filtrate concentrating obtains the pure product 2-of 20g (2 '-p-methoxy-phenyl amino)-4,5-dichloro pyrimidine 13 (productive rate: 81%)
Proton nmr spectra
1H-NMR (CDCl
3, 400MHz): δ 8.31-8.28 (m, 2H), 7.81 (s, 1H), 6.98-6.91 (m, 2H), 6.84-6.82 (m, 1H), 3.82 (s, 3H); MS (ESI) m/e (M+H
+) 270.
(13.2-2 '-p-methoxy-phenyl amino)-4, the synthesis technique two of 5-dichloro pyrimidine 13
(23.0g 91.4mmol) joins in the phosphorus oxychloride of 300mL in batches, then reaction mixture is heated to backflow, and reaction solution stirred 2 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12.Excessive phosphorus oxychloride under reduced pressure distilled remove, the crude product that obtains is dissolved in ethyl acetate.Organic phase is used anhydrous sodium sulfate drying after washing with saturated sodium bicarbonate aqueous solution.Remove by filter siccative, filtrate concentrating obtains the pure product 2-of 18g (2 '-p-methoxy-phenyl amino)-4,5-dichloro pyrimidine 13 (productive rate: 73%)
(14.2-2 '-p-methoxy-phenyl amino)-4, the synthesis technique three of 5-dichloro pyrimidine 13
(23.0g 91.4mmol) joins in the phosphorus oxychloride of 300mL in batches, then reaction mixture is heated to backflow, and reaction solution stirred 4 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12.Excessive phosphorus oxychloride under reduced pressure distilled remove, the crude product that obtains is dissolved in ethyl acetate.Organic phase is used anhydrous sodium sulfate drying after washing with saturated sodium bicarbonate aqueous solution.Remove by filter siccative, filtrate concentrating obtains the pure product 2-of 17g (2 '-p-methoxy-phenyl amino)-4,5-dichloro pyrimidine 13 (productive rate: 69%)
15.2-the synthesis technique one of methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14
With 2-(2 '-p-methoxy-phenyl amino)-4, (10g, 37mmol) (5g 14.6mmol) joins in the butanol solution of 2.5L heating for dissolving to 5-dichloro pyrimidine 13 with amine 7.Drip the ethyl acetate solution (20mL) of 4M hydrogenchloride then.Reaction solution is heated to backflow, and stirs 2 hours under this temperature.Reaction solution is cooled to 100 ℃ then, adds 2-(2 '-p-methoxy-phenyl amino)-4, (5g, 18.5mmol) and the ethyl acetate solution (10mL) of 4M hydrogenchloride, this stirs reaction solution 2 hours under reflux temperature 5-dichloro pyrimidine 13 again.When the detection reaction end, reaction solution concentrates to be done.Crude product washs with ethyl acetate, obtains 4g product 2-methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14 (productive rate: 47%) with recrystallizing methanol then
Proton nmr spectra
1H-NMR (CDCl
3, 400MHz): δ 10.46 (s, 1H), 8.59-8.56 (m, 1H), 8.28-8.26 (m, 1H), 8.04 (s, 1H), 7.38 (s, 1H), 7.02 (d, J=8.8Hz, 1H), 6.94-6.90 (m, 2H), 6.85-6.83 (m, 1H), 4.48 (s, 2H), 3.84 (s, 3H), 3.27-3.24 (m, 2H), 3.14 (s, 3H), 2.72-2.69 (m, 11H), 2.24 (s, 3H), and 1.97-1.90 (m, 2H), 1.66-1.56 (m, 2H); MS (ESI) m/e (M+H
+) 577.
16.2-the synthesis technique two of methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14
With 2-(2 '-p-methoxy-phenyl amino)-4, (10g, 37mmol) (5g 14.6mmol) joins in the aqueous isopropanol of 2.5L heating for dissolving to 5-dichloro pyrimidine 13 with amine 7.Drip the ethyl acetate solution (20mL) of 4M hydrogenchloride then.Reaction solution is heated to backflow, and stirs 2 hours under this temperature.Reaction solution is cooled to 100 ℃ then, adds 2-(2 '-p-methoxy-phenyl amino)-4, (5g, 18.5mmol) and the ethyl acetate solution (10mL) of 4M hydrogenchloride, this stirs reaction solution 2 hours under reflux temperature 5-dichloro pyrimidine 13 again.When the detection reaction end, reaction solution concentrates to be done.Crude product washs with ethyl acetate, obtains 2g product 2-methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14 (productive rate: 24%) with recrystallizing methanol then
17.2-the synthesis technique three of methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14
With 2-(2 '-p-methoxy-phenyl amino)-4, (10g, 37mmol) (5g 14.6mmol) joins in the butanol solution of 2.5L heating for dissolving to 5-dichloro pyrimidine 13 with amine 7.Drip the ethyl acetate solution (20mL) of 4M hydrogenchloride then.Reaction solution is heated to backflow, and stirs 4 hours under this temperature.Reaction solution is cooled to 100 ℃ then, adds 2-(2 '-p-methoxy-phenyl amino)-4, (5g, 18.5mmol) and the hydrogenchloride ethyl acetate solution (10mL) of 4M, this stirs reaction solution 4 hours under reflux temperature 5-dichloro pyrimidine 13 again.When the detection reaction end, reaction solution concentrates to be done.Crude product washs with ethyl acetate, obtains 3.5g product 2-methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14 (productive rate: 42%) with recrystallizing methanol then
Claims (7)
1. 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-and 4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) synthetic method of 1-isoindolinone, may further comprise the steps:
The first step: with 2,4,5-trichloropyrimidine
1Be raw material, by generating intermediate 2,5-two chloro-4-methylthiopyrimidines with sodium methyl mercaptide aqueous solution generation substitution reaction
2
Second step: 2,5-, two chloro-4-methylthiopyrimidines
2Under the HCl/BuOH/ reflux conditions with aromatic amine
3Take place to generate intermediate 2-aromatic amino-4-methylthio group-5-chloropyrimide after the substitution reaction
4
The 3rd step: then 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 is generated intermediate 2-aromatic amino-4-hydroxyl-5-chloropyrimide after hydrolysis under the HCl/ reflux conditions
5;
The 4th step: 2-aromatic amino-4-hydroxyl-5-chloropyrimide
5Under the phosphorus oxychloride effect, generate 2-aromatic amino-4,5-dichloro pyrimidine
6
The 5th step: last 2-aromatic amino-4,5-dichloro pyrimidine
6Under the ethyl acetate solution of hydrogenchloride and n-BuOH effect with amine
7Substitution reaction takes place obtain 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone
8
Chemical equation is as follows:
2. 2-aromatic amino-4, the synthetic method of 5-dichloro pyrimidine may further comprise the steps:
The first step: with 2,4,5-trichloropyrimidine
1Be raw material, by generating intermediate 2,5-two chloro-4-methylthiopyrimidines with sodium methyl mercaptide aqueous solution generation substitution reaction
2
Second step: 2,5-, two chloro-4-methylthiopyrimidines
2Under the HCl/BuOH/ reflux conditions with aromatic amine
3Take place to generate intermediate 2-aromatic amino-4-methylthio group-5-chloropyrimide after the substitution reaction
4
The 3rd step: then with 2-aromatic amino-4-methylthio group-5-chloropyrimide
4After hydrolysis under the HCl/ reflux conditions, generate intermediate 2-aromatic amino-4-hydroxyl-5-chloropyrimide
5
The 4th step: 2-aromatic amino-4-hydroxyl-5-chloropyrimide
5Under the phosphorus oxychloride effect, generate 2-aromatic amino-4,5-dichloro pyrimidine 6; Reaction formula is as follows
3. synthetic method according to claim 1 and 2 is characterized in that, the first step reaction is with 2,4, the 5-trichloropyrimidine
1Be dissolved in organic solvent and be selected from a kind of in tetrahydrofuran (THF), acetonitrile or the Virahol, then the sodium methyl mercaptide aqueous solution slowly is added drop-wise in the reaction solution, dropwises, reaction solution at room temperature stirred 12～24 hours, obtain pure product 2 after the aftertreatment, 5-two chloro-4-methylthiopyrimidines
2
4. synthetic method according to claim 1 and 2 is characterized in that, the reaction of second step is with 2,5-two chloro-4-methylthiopyrimidines
2And aromatic amine
3Be dissolved in propyl carbinol or Virahol, ethyl acetate solution with hydrogenchloride slowly is added drop-wise in the reaction solution then, dropwises, and reaction solution is heated to reflux temperature, and under this temperature, stirred 16～24 hours, obtain pure product 2-aromatic amino-4-methylthio group-5-chloropyrimide after the aftertreatment
4
5. synthetic method according to claim 1 and 2 is characterized in that, three-step reaction is with 2-aromatic amino-4-methylthio group-5-chloropyrimide
4Join aqueous hydrochloric acid, then reaction solution is heated to backflow, reaction solution stirred under this temperature 12～16 hours, obtained pure product 2-aromatic amino-4-hydroxyl-5-chloropyrimide after the aftertreatment
5
6. synthetic method according to claim 1 is characterized in that, four-step reaction is with 2-aromatic amino-4-hydroxyl-5-chloropyrimide
5Join in the phosphorus oxychloride in batches, then reaction mixture is heated to backflow, reaction solution stirred under this temperature 1～4 hour, obtained pure product 2-aromatic amino-4 after the aftertreatment, the 5-dichloro pyrimidine
6.
7. according to the described 2-methyl of claim 1-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) synthetic method of 1-isoindolinone, it is characterized in that, the reaction of the 5th step is with 2-aromatic amino-4, the 5-dichloro pyrimidine
6And amine
7Join in propyl carbinol or the aqueous isopropanol, heating for dissolving drips the ethyl acetate solution of hydrogenchloride then, and reaction solution is heated to backflow, and stirs 2-4 hour under this temperature, reaction solution is cooled to 100 ℃ then, adds 2-aromatic amino-4, the 5-dichloro pyrimidine
6Ethyl acetate solution with hydrogenchloride, this stirs reaction solution 2-4 hour under reflux temperature again, obtains product 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino behind the recrystallization)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone
8
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