CN112939995A - Process for preparing dioxanoquinazoline derivatives - Google Patents
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Abstract
A preparation method of dioxane quinazoline derivatives, belonging to the synthesis research of drug intermediates. The method has the advantages of mild reaction, high yield and the like compared with the reported synthetic method. The R group is methyl, ethyl, propyl, isopropyl, methoxyethyl, ethoxypropyl, N-dimethylaminopropyl, tetrahydrofuran-3-oxyl, 1-methylpiperidine-4-methyl, 3-pyrrolidinopropyl, 3-cyclohexylpropoxy and ethyl sulfide.
Description
Technical Field
The invention belongs to the field of synthesis of drug intermediates, and relates to a preparation method of a dioxane quinazoline derivative. In particular to 2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline derivatives with different substituents.
Background
Tumors are abnormal masses of tissue that grow too rapidly and fail to work synergistically with normal tissues. Cancer, malignant tumor, is a common and frequently encountered disease that seriously threatens human health, and the mortality rate of the cancer is second to cardiovascular diseases, which is the second most common disease causing human death. Despite the tremendous advances in research in the cancer field, the world health organization estimates that the threat of cancer to human health continues to escalate (Kim Y T, Park S W, Kim J W. correction world expression of EGFR and the diagnosis of diseases with biological cancer [ J ]. Gynecol Oncol.2002,87(1): 84-89.). This persistent high-incidence state of cancer is predictive of its imminent first killer of human health and is a major challenge to global public health. The targeted therapy is a new treatment means which is more accurate than chemotherapy, so the side effect is far less than that of chemotherapy, and the effect is more obvious than that of chemotherapy. For patients with high sensitivity, targeted drug therapy does control the disease, effectively improves the quality of life, and prolongs the life of the patient (Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med.2010.362(25): 2380-8.). The principle of this treatment is the use of small molecules with specific proteins that are resistant to cancer abnormalities or disorders. Under the premise of competing with ATP, the ATP specifically blocks the binding with a kinase capsule, blocks a downstream signal path, further inhibits the proliferation and differentiation of tumor cells, and is a treatment method aiming at the identified oncogenic sites on a cellular and molecular level. (Ito, Fumiaki. form Target Therapy for Cancer: Anti-Cancer Drugs Targeting Growth-Factor signalling Molecules [ J ]. Biological & Pharmaceutical Bulletin,2011,34(12): 1773.). The medicine can kill cancer cells without damaging surrounding normal cells. Wherein, the small molecule tyrosine kinase is widely researched as a specific small molecule targeted drug.
Quinazoline is a very Important nitrogen-containing heterocyclic compound, and through a large number of researches, a compound containing a Quinazoline ring has antibacterial, anti-inflammatory, anti-diabetic, anti-tuberculosis, anti-HIV, anti-tumor effects (VijaychandA, ManJuulaEN, Bharathhen, et. medicinal. and biological logic of cancer of Quinazoline: A highlyImport functional for Drug Discovery: A Review [ J ]. Int J Pharma Bio Sci,2011,2(1): 780-809.). Because of its pharmacological and biological activity, it is a hot research in the pharmaceutical chemistry field. So far, most of more than 20 tinib antitumor drugs comprise quinazoline compounds Erlotinib (I), Gefitinib (II), Ico-tinib (III), lapatinb (IV) and He Afatinib (V), and have obvious clinical curative effects. There are still many anti-tumor quinazoline derivatives in clinical and preclinical research stages.
The quinazoline derivative becomes an anti-tumor small molecule in targeted therapy research of a tyrosine kinase inhibitor, and has good activity and selectivity in anti-tumor biological activity. Related research and synthetic routes are more and more mature, but the existing synthetic methods and routes are relatively limited, and the problems of complicated routes, low yield and the like exist. Therefore, the synthetic route of the 2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline derivative has important research significance. The reported synthetic routes (Qin X., Li Z., Yang L., Liu P., Hu L., Zeng C., Pan Z. discovery of new [1,4] dioxino [2,3-f ] quinazoline-based inhibitors of EGFR cloning the T790M/L858R mutant. bioorg Med Chem. (2016); 24(13): 2871-2881.):
disclosure of Invention
The invention provides a synthetic route of a 10-chloro-5-substituent-2, 3-dihydro- [1,4] dioxane- [2,3-f ] quinazoline compound formula in a drug intermediate. The method of the invention uses common reagents and conventional production conditions in industry, and has mild reaction conditions and simple steps.
A method for synthesizing a 10-chloro-5-substituent-2, 3-dihydro- [1,4] dioxane- [2,3-f ] quinazoline compound of a dioxanoquinazoline derivative, which is characterized by comprising the following steps:
step (a): preparation of methyl 8-hydroxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Pd (COD) (CH)2TMS)2And 2- (di-1-adamantylphosphine) -1- (2, 6-diisopropylphenyl) -1H imidazole were added to a Schlenk's tube, sealed with a septum, and 8-bromo-2, 3-dihydrobenzo [ b ] was added using a syringe][1,4]After the reaction of the mixture of dioxane-5-methyl formate and tetrahydrofuran was completed, the mixture was extracted with diethyl ether, cooled and filtered to form complex 1. Adding the complex 1 into a Schlenk tube, then adding tetrahydrofuran, mixing and stirring, and then addingnBu4NOH. After 20 minutes of reaction, acetic acid was added and stirred for 20 minutes. Extracting and vacuum concentrating to obtain 8-hydroxy-2, 3-dihydrobenzo [ b][1,4]Dioxane-5-carboxylic acid methyl ester.
Step (b): preparation of methyl 8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Dissolving 8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-methyl formate in DMF, adding anhydrous potassium carbonate, stirring for 5 minutes, heating to 70 ℃, dropwise adding methyl iodide into the system until the reaction is finished, pouring the mixed solution into ice water, extracting with ethyl acetate for three times, washing with saturated saline solution for three times, and concentrating to obtain a white solid.
Step (c): preparation of 8-methoxy-6-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-methyl formate the preparation of 8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-methyl formate acetic acid is dissolved, stirred for half an hour under the ice bath condition, the system temperature is kept below 5 ℃, concentrated nitric acid is slowly dripped into the system, after the reaction is finished, the mixed solution is poured into ice water, yellow solid is separated out, the mixed solution is washed three times by ice water, and the extraction filtration and the column chromatography separation are carried out.
Step (d): preparation of methyl 6-amino-8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Dissolving 8-methoxy-6-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-methyl formate in ethanol, adding a proper amount of palladium carbon, reacting for 8-10h in a hydrogen environment, and filtering after the reaction is finished to directly carry out the next reaction.
Step (e) preparation of 5-methoxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazolin-10 (9H) -one
And adding formamidine acetate into the solution after hydrogenation reduction, and carrying out reflux reaction for 6-8h to separate out a white solid. After the reaction is finished, filtering, washing with ethyl acetate for three times to obtain the 5-methoxy-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline-10 (9H) -ketone, wherein the total yield of the two steps is more than 70%.
Step (f): preparation of 10-chloro-5-methoxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazoline
Dissolving 5-methoxy-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline-10 (9H) -ketone in phosphorus oxychloride, heating to reflux reaction for 4-6H, detecting the reaction progress by TLC, cooling to room temperature after the reaction is finished, pouring the reaction liquid into ice water, neutralizing to neutrality by potassium carbonate, extracting by ethyl acetate for three times, concentrating under reduced pressure, separating and purifying by a silica gel column, and concentrating to obtain an off-white product.
Step (g): preparation of 10-chloro-5-hydroxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazolin-10 (9H) -one
Dissolving a compound 5-methoxy-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline-10 (9H) -ketone in dichloromethane, slowly dropwise adding aluminum trichloride into the system, and reacting at room temperature for at least 12H; removing solvent by distillation, hydrolyzing the residue with sodium hydroxide solution, acidifying the obtained solution with hydrochloric acid, and extracting with ethyl acetate to obtain 10-chloro-5-hydroxy-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazolin-10 (9H) -one; the molar ratio of 5-methoxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazolin-10 (9H) -one to aluminum trichloride is 1: 3;
a step (h): preparation of dioxanoquinazoline derivatives
Dissolving 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazoline-5-alcohol in DMF, adding potassium carbonate, stirring at normal temperature for half an hour until the solution is completely dissolved, heating to 60-90 ℃, then dropwise adding R-X into the system, reacting for 6-8h, and detecting the reaction process by TlC. After the reaction is finished, pouring the reactant into 50mL of ice water, and performing suction filtration to obtain a series of dioxane quinazoline derivatives; r in R-X is the same as below, and X is halogen; preferably 1-2mmol of R-X per 1mmol of 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-ol;
r is straight-chain or branched alkane, nitrogen-substituted straight-chain alkane, alkoxy-substituted straight-chain or branched alkane, saturated cycloalkane-substituted straight-chain alkane, and nitrogen-oxygen-containing saturated heterocyclic group-substituted straight-chain or branched alkane. If R is methyl, step (g) and step (h) may not be performed.
Reaction conditions are as follows: pd (COD) (CH)2TMS)2,nBu4NOHTHF,AcOH,tr,20h；b.THF,NaOH,0℃,1h；c.DMF,CH3I,KHCO3,rt；d.HOAc,HNO3,0℃；e.Pd/C,H2,C2H5OH,rt；f.C2H5OH,Formamidineacetate,reflux；g.POCl3,reflux,100℃,4h；h.CH2Cl2,AlCl3,rt,12h；i.R-X,K2CO3,80℃；
Detailed Description
The present invention will be further illustrated with reference to the following examples, but the present invention is not limited to the following examples.
Example 1
Step (a): preparation of methyl 8-hydroxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Pd (COD) (CH)2TMS)2(203mg, 0.52mmol) and 2- (bis-1-adamantylphosphine) -1- (2, 6-diisopropylphenyl) -1H imidazole (209mg, 0.55mmol) were added to a 5mL Schlenk's tube, sealed with a septum, and 8-bromo-2, 3-dihydrobenzo [ b ] was added via syringe][1,4]A mixture of dioxane-5-carboxylic acid methyl ester (148mg,0.55mmol) and 2mL tetrahydrofuran was reacted and extracted with diethyl ether and filtered to yield 312mg of complex 1. Adding the complex 1(16.4mg, 2mmol) into a Schlenk tube, adding 1mL of tetrahydrofuran, mixing and stirring, addingnBu4NOH(27.4mg,3.43·10-2mmol). After 20 minutes of reaction, 0.5ml of acetic acid was added and stirred for 20 minutes. Extracting and vacuum concentrating to obtain 143mg of 8-hydroxy-2, 3-dihydrobenzo [ b ]][1,4]Dioxane-5-carboxylic acid methyl ester. Yield: 74 percent.
Step (b): preparation of methyl 8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Reacting 8-hydroxy-2, 3-dihydrobenzo [ b ]][1,4]Dioxane-5-methyl formate (420mg, 2mmol) is dissolved in 15mL of DMF, anhydrous potassium carbonate (828mg, 8mmol) is added, stirring is carried out for 5 minutes, heating is carried out to 70 ℃, methyl iodide (0.148mL,2.4mmol) is added dropwise to the system, after the reaction is finished, the mixed solution is poured into ice water, extraction is carried out for three times by ethyl acetate, saturated saline solution is washed for three times, and white solid is obtained by concentration.1H NMR(CDCl3,400MHz):δ3.78(s,3H),3.95(s,3H),4.28(s,4H),6.77(d,1H),7.69(d,1H).MS：225(M+H)+.
Step (c): preparation of methyl 8-methoxy-6-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Step (c): reacting 8-methoxy-2, 3-dihydrobenzo [ b ]][1,4]Dissolving dioxane-5-methyl formate (448mg, 2mmol) in 15mL acetic acid, stirring for half an hour under ice bath condition, keeping the temperature of the system below 5 ℃, and slowly dropping into the system15mL of concentrated nitric acid, pouring the mixed solution into ice water after the reaction is finished, separating out yellow solid, washing with ice water for three times, filtering, and performing column chromatography to obtain 408mg of a pure product of 8-substituted oxy-6-nitro-2, 3-dihydrobenzo [ b ]][1,4]Dioxane-5-carboxylic acid methyl ester. Yield: 75 percent.1H NMR(CDCl3,400MHz):δ3.87(s,3H),3.99(s,3H),4.37-4.39(m,2H),4.43-4.45(m,2H),7.41(s,1H).MS：225(M+H)+.
Step (d): preparation of methyl 6-amino-8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Reacting 8-substituted oxy-6-nitro-2, 3-dihydrobenzo [ b ]][1,4]Dissolving dioxane-5-methyl formate (478mg, 2mmol) in 15mL ethanol, adding a proper amount of palladium carbon, reacting for 8-10h in a hydrogen environment, filtering the palladium carbon after the reaction is finished, and directly carrying out the next reaction without concentration.1H NMR(CDCl3,400MHz):δ3.87(s,3H),3.88(s,3H),4.27-4.29(m,2H),4.33-4.35(m,2H),5.32(s,2H),5.84(s,1H).MS：225(M+H)+.
A step (e): preparation of 5-hydroxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazolin-10 (9H) -one
Formamidine acetate (312mg, 3mmol) was added to the above solution after the hydrogenation reduction, and the reaction was refluxed for 6-8h to precipitate a white solid. After the reaction was completed, the reaction mixture was filtered and washed with ethyl acetate three times to obtain 327mg of 5-methoxy-2, 3-dihydro- [1,4]]Dioxane [2,3-f ]]Quinazoline-10 (9H) -one, the total yield of the two steps is more than 70%.1H NMR(CDCl3,400MHz):δ3.87(s,3H),4.28-4.32(m,4H),6.75(s,1H),7.85(s,1H),11.75(s,1H).MS：225(M+H)+.
Step (f): preparation of 10-chloro-5-methoxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazoline
Will use 10-chloro-5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Dissolving quinazoline (468mg, 2mmol)10mL phosphorus oxychloride, heating to reflux reaction for 4-6h, detecting the reaction process by TlC, cooling to room temperature after the reaction is finished, pouring the reaction liquid into ice water, neutralizing with potassium carbonate to neutrality, extracting with ethyl acetate for three times, concentrating under reduced pressure, separating and purifying through a silica gel column, and concentrating to obtain 342mg of off-white product 10-chloro-5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]A quinazoline.1H NMR(CDCl3,400MHz,δppm):δ4.07(s,3H),4.50(s,4H),7.09(s,1H),8.81(s,1H).MS：253(M+H)+.
Example 2
Preparation of 10-chloro-5-ethoxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazoline (I-2)
Steps (a) - (f) are the same as in example 1
Step (g): preparation of 10-chloro-5-hydroxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazolin-10 (9H) -one
Mixing 10-chloro-5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Dissolving quinazoline-10 (9H) -ketone (504mg, 2mmol) in 15mL dichloromethane, slowly adding aluminum trichloride (798mg, 6mmol) dropwise into the system, and reacting at room temperature for at least 12H; removing the solvent by distillation, hydrolyzing the residue with sodium hydroxide solution, acidifying the solution with hydrochloric acid, and extracting with ethyl acetate to obtain 428mg of 10-chloro-5-hydroxy-2, 3-dihydro- [1,4]]Dioxane [2,3-f ]]Quinazolin-10 (9H) -one; yield: 90 percent.1H NMR(CDCl3,400MHz):δ11.65(s,1H),7.55(s,1H),6.10(s,1H),4.28(s,4H),4.07(s,3H).MS:253(M+H)+.
Step h: preparation of 10-chloro-5-ethoxy-2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]And (2) adding 15mL of DMF (dimethyl formamide) to dissolve 4 quinazoline-5-alcohol (476mg,2mmol), adding potassium carbonate (552mg,4mmol), stirring at normal temperature for half an hour until complete dissolution, dropwise adding 95 mu l of bromoethane and 3mmol into the system, heating to 90 ℃, reacting for 8 hours, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice water, followed by suction filtration to obtain 400mg of 10-chloro-5-ethoxy-2, 3-dihydro- [1,4]]Dioxy [2,3-f ]]A quinazoline; white solid, yield: 89 percent.1H NMR(CDCl3,400MHz):δ9.56(s,1H),7.11(s,1H),4.28(s,4H),4.03(q,2H),1.40(t,3H).MS:267(M+H)+.
Example 3
Preparation of 10-chloro-5-propoxy-2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline (VIII-3)
Steps (a) - (f) are the same as in example 1
Step g same as example 2
Step h: preparation of 10-chloro-5-propoxy-2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Quinazoline (476mg,2mmol) is dissolved by 15ml DMF, potassium carbonate (552mg,4mmol) is added, stirring is carried out for half an hour at normal temperature until complete dissolution, bromopropane (284 mu l,3mmol) is dropwise added into the system, heating is carried out to 90 ℃, reaction is carried out for 8h, and the reaction progress is detected by TlC. After the reaction, the reaction mixture was poured into 50mL of ice-water and filtered under suction to obtain 410mg of 10-chloro-5-propoxy-2, 3-dihydro- [1,4]]Dioxy [2,3-f ]]A quinazoline; white solid, yield: 87 percent.1H NMR(CDCl3,400MHz):δ9.56(s,1H),7.11(s,1H),4.28(s,4H),4.00(t,2H),1.75(m,2H),0.98(t,3H).MS:281(M+H)+.
Example 4
Preparation of 10-chloro-5-isopropoxy-2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline (VIII-4)
Steps (a) - (f) are the same as in example 1
Step g same as example 2
Step h: preparation of 10-chloro-5-isopropoxy-2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazoline-5-ol (476mg,2mmol) by 15ml DMF, adding potassium carbonate (552mg,4mmol), stirring at normal temperature for half an hour until complete dissolution, dropwise adding 2-bromopropane (284 mu l,3.0mmol) into the system, heating to 80 ℃, reacting for 12h, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice water and filtered under suction to obtain 450mg of 10-chloro-5-isopropoxy-2, 3-dihydro- [1,4]]Dioxy [2,3-f ]]A quinazoline; white solid, yield: 89 percent.1H NMR(CDCl3,400MHz):δ9.56(s,1H),7.21(s,1H),4.66(m,1H),4.28(s,4H),1.22(d,6H).MS:281(M+H)+.
Example 5
Preparation of 10-chloro-5- (2-methoxyethoxy) -2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline (VIII-5)
Steps (a) - (f) are the same as in example 1
Step (g) same as example 2
Step h: preparation of 10-chloro-5- (2-methoxyethoxy) -2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazoline-5-ol (476mg,2mmol) by 15ml DMF, adding potassium carbonate (552mg,4mmol), stirring at normal temperature for half an hour until the potassium carbonate is completely dissolved, then slowly adding 1-chloro-2-methoxyethane (264mg,3mmol) into the system, heating to 85 ℃, reacting for 12h, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice water and filtered under suction to obtain 444mg of 10-chloro-5- (2-methoxyethoxy) -2, 3-dihydro- [1,4]]Dioxy [2,3-f ]]Quinazoline 420mg(ii) a White solid, yield: 86 percent.1H NMR(CDCl3,400MHz):δ9.56(s,1H),7.21(s,1H),4.23(m,2H),4.28(s,4H),3.75(t,2H),3.32(s,3H).MS:297(M+H)+
Example 6
Preparation of 10-chloro-5- (3-ethoxypropoxy) -2, 3-dihydro- [1,4] dioxa [2,3-f ] quinazoline (VIII-6)
Steps (a) - (f) are the same as in example 1
Step (g) same as example 2
Step h: preparation of 10-chloro-5- (3-ethoxypropoxy) -2, 3-dihydro- [1,4] dioxa [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazolin-5-ol (476mg,2mmol) with 15ml DMF, adding potassium carbonate (552mg,4mmol), stirring at normal temperature for half an hour until completely dissolving, then slowly adding 1-chloro-3-ethoxypropane (369mg,3mmol) into the system, heating to 90 ℃, reacting for 12h, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice water and filtered under suction to obtain 390mg of 10-chloro-5- (3-ethoxypropoxy) -2, 3-dihydro- [1,4]]Dioxa [2,3-f]A quinazoline; white solid, yield: 79 percent.1H NMR(CDCl3,400MHz):δ9.56(s,1H),7.21(s,1H),4.39(m,2H),4.28(s,4H),3.45(m,2H),3.32(t,2H),2.01(m,2H),1.02(t,3H).MS:325(M+H)+.
Example 7
Preparation of 3- ((10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-yl) oxy) -N, N-dimethylpropane-1-amine (VIII-7)
Steps (a) - (f) are the same as in example 1
Step (g) same as example 1
Step h: preparation of 3- ((10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-yl) oxy) -N, N-dimethylpropane-1-amine
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazoline-5-ol (476mg,2mmol) by using 15ml DMF, adding potassium carbonate (552mg,4mmol), stirring for half an hour at normal temperature until the potassium carbonate is completely dissolved, then slowly adding 3-chloro-1- (N, N-dimethyl) propylamine (363mg,3mmol) into the system, heating to 90 ℃, reacting for 12h, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice water, followed by suction filtration to obtain 390mg of 3- ((10-chloro-2, 3-dihydro- [1, 4)]Dioxo [2, 3-f)]Quinazolin-5-yl) oxy) -N, N-dimethylpropane-1-; white solid, yield: 80 percent.1H NMR(CDCl3,400MHz):δ9.53(s,1H),7.21(s,1H),4.28(s,4H),4.10(t,2H),2.34(t,2H),2.15(s,6H),1.82(m,2H).MS:324(M+H)+.
Example 8
Preparation of 10-chloro-5- ((tetrahydrofuran-3-yl) oxy) -2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline (VIII-8)
Steps (a) - (f) are the same as in example 1
Step (g) same as example 1
Step h: preparation of 10-chloro-5- ((tetrahydrofuran-3-yl) oxy) -2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazoline-5-ol (476mg,2mmol) by 15mL DMF, adding potassium carbonate (552mg,4mmol), stirring at normal temperature for half an hour until the potassium carbonate is completely dissolved, then slowly adding 3-chlorotetrahydrofuran (378mg,3.55mmol) into the system, heating to 80 ℃, reacting for 12h, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice water and filtered under suction to obtain 376mg of 10-chloro-5- ((tetrahydrofuran-3-yl) oxy) -2, 3-dihydro- [1, 4%]Dioxy [2,3-f ]]370mg of quinazoline; white solid, yield: 76 percent.1HNMR(CDCl3,400MHz):δ9.53(s,1H),7.21(s,1H),4.28(s,4H),4.10(m,2H),4.02(m,1H),3.34(m,2H),2.15(m,2H).MS:309(M+H)+.
Example 9
Preparation of 10-chloro-5- ((1-methylpiperidin-4-yl) methoxy) -2, 3-dihydro- [1,4] dioxa [2,3-f ] quinazoline (VIII-9)
Steps (a) - (f) are the same as in example 1
Step (g) same as example 1
Step h: preparation of 10-chloro-5- ((1-methylpiperidin-4-yl) methoxy) -2, 3-dihydro- [1,4] dioxa [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazolin-5-ol (476mg,2mmol) with 15ml DMF, adding potassium carbonate (552mg,4mmol), stirring at room temperature for half an hour until completely dissolving, then slowly adding 4- (chloromethyl) -1-methylpiperidine (440mg,3mmol) into the system, heating to 80 deg.C, reacting for 12h, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice water, followed by suction filtration to obtain 285mg of 10-chloro-5- ((1-methylpiperidin-4-yl) methoxy) -2, 3-dihydro- [1, 4%]Dioxa [2,3-f]A quinazoline; white solid, yield: 60 percent.1H NMR(CDCl3,400MHz):δ9.53(s,1H),7.21(s,1H),4.28(s,4H),4.10(d,2H),2.53(m,4H),2.15(m,3H),2.01(m,1H),1.45(m,4H).MS:350(M+H)+.
Example 10
Preparation of 10-chloro-5- (3- (pyrrolidin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazoline (VIII-10)
Steps (a) - (f) are the same as in example 1
Step (g) same as example 1
Step h: preparation of 10-chloro-5- (3- (pyrrolidin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazolin-5-ol (476mg,2mmol) with 15ml DMF, adding potassium carbonate (552mg,4mmol), stirring at room temperature for half an hour until completely dissolving, and slowly adding 1- (3-chloropropyl) pyridine into the systemPyrrolidine (441mg,3mmol) is heated to 80 ℃ and reacted for 12h, and the reaction progress is detected by TlC. After the reaction is finished, the reactant is poured into 50mL of ice water and is filtered by suction to obtain 10-chloro-5- (3- (pyrrolidine-1-yl) propoxy) -2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]310mg of quinazoline; white solid, yield: 66 percent.1H NMR(CDCl3,400MHz):δ9.65(s,1H),7.35(s,1H),4.28(s,4H),4.04(t,2H),2.51(m,4H),2.34(t,2H),1.82(m,2H),1.65(m,4H).MS:350(M+H)+
Example 11
Preparation of 10-chloro-5- (3-cyclohexylpropoxy) -2, 3-dihydro- [1,4] dioxa [2,3-f ] quinazoline (VIII-11)
Steps (a) - (f) are the same as in example 1
Step (g) same as example 1
Step h: preparation of 10-chloro-5- (3-cyclohexylpropoxy) -2, 3-dihydro- [1,4] dioxa [2,3-f ] quinazoline
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazoline-5-ol (476mg,2mmol) by 15ml DMF, adding potassium carbonate (552mg,4mmol), stirring at normal temperature for half an hour until the potassium carbonate is completely dissolved, then slowly adding (3-chloropropyl) cyclohexane (480mg,3mmol) into the system, heating to 85 ℃, reacting for 12 hours, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice-water and filtered under suction to obtain 340mg of 10-chloro-5- (3-cyclohexylpropoxy) -2, 3-dihydro- [1,4]]Dioxa [2,3-f]A quinazoline; white solid, yield: 70 percent.1H NMR(CDCl3,400MHz):δ9.65(s,1H),7.35(s,1H),4.28(s,4H),4.04(t,2H),1.75(m,2H),1.62(m,4H),1.50(m,4H),1.32(m,2H),1.12(m,2H),MS:363(M+H)+.
Example 12
Preparation of 10-chloro-5- (2- (methylthio) ethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-f ] quinazoline
Steps (a) - (f) are the same as in example 1
Step (g) same as example 1
Step h: preparation of 4- ((10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-yl) oxy) methyl) -N-methylpiperidine-1-carboxamide
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Dissolving quinazoline-5-ol (476mg,2mmol) by using 15mL DMF, adding potassium carbonate (552mg,4mmol), stirring at normal temperature for half an hour until the potassium carbonate is completely dissolved, then slowly adding 2-chloroethyl ethyl sulfide (372mg,3mmol) into the system, heating to 80 ℃, reacting for 12h, and detecting the reaction progress by TlC. After the reaction, the reaction mixture was poured into 50mL of ice-water and filtered with suction to obtain 405mg of 10-chloro-5- (2- (methylthio) ethoxy) -2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]A quinazoline; white solid, yield: 65 percent.1H NMR(CDCl3,400MHz:δ9.56(s,1H),7.21(s,1H),4.39(m,2H),4.28(s,4H),3.45(m,2H),3.32(t,2H),2.01(m,2H),1.02(t,3H).MS:325(M+H)+.
Claims (1)
1. A method for synthesizing a 10-chloro-5-substituent-2, 3-dihydro- [1,4] dioxane- [2,3-f ] quinazoline compound of a dioxanoquinazoline derivative is characterized by comprising the following steps:
step (a): preparation of methyl 8-hydroxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Pd (COD) (CH)2TMS)2And 2- (di-1-adamantylphosphine) -1- (2, 6-diisopropylphenyl) -1H imidazole were added to a Schlenk's tube, sealed with a septum, and 8-bromo-2, 3-dihydrobenzo [ b ] was added using a syringe][1,4]After the reaction of the mixture of dioxane-5-methyl formate and tetrahydrofuran was completed, the mixture was extracted with diethyl ether, cooled and filtered to form complex 1. Adding the complex 1 into a Schlenk tube, then adding tetrahydrofuran, mixing and stirring, and then addingnBu4NOH. After 20 minutes of reaction, acetic acid was added and stirred for 20 minutes. Extracting and vacuum concentrating to obtain 8-hydroxy-2, 3-dihydrobenzo [ b][1,4]Dioxane-5-carboxylic acid methyl ester;
step (b): preparation of methyl 8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Dissolving 8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-methyl formate in DMF, adding anhydrous potassium carbonate, stirring for 5 minutes, heating to 70 ℃, dropwise adding iodomethane into the system until reaction is finished, pouring the mixed solution into ice water, extracting with ethyl acetate for three times, washing with saturated saline solution for three times, and concentrating to obtain a white solid;
step (c): preparation of methyl 8-methoxy-6-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Dissolving 8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-methyl formate in acetic acid, stirring for half an hour under an ice bath condition, keeping the temperature of the system below 5 ℃, slowly dropwise adding concentrated nitric acid into the system, pouring the mixed solution into ice water after the reaction is finished, separating out yellow solid, washing with ice water for three times, carrying out suction filtration, and carrying out column chromatography separation;
step (d): preparation of methyl 6-amino-8-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate
Dissolving 8-methoxy-6-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-methyl formate in ethanol, adding a proper amount of palladium carbon, reacting for 8-10h in a hydrogen environment, and filtering after the reaction is finished to directly carry out the next reaction;
step (e) preparation of 5-methoxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazolin-10 (9H) -one
And adding formamidine acetate into the solution after hydrogenation reduction, and carrying out reflux reaction for 6-8h to separate out a white solid. After the reaction is finished, filtering, washing with ethyl acetate for three times to obtain 5-methoxy-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline-10 (9H) -ketone;
step (f): preparation of 10-chloro-5-methoxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazoline
Dissolving 5-methoxy-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline-10 (9H) -ketone in phosphorus oxychloride, heating to reflux reaction for 4-6H, detecting the reaction process by TLC, cooling to room temperature after the reaction is finished, pouring the reaction liquid into ice water, neutralizing to neutrality by potassium carbonate, extracting by ethyl acetate for three times, concentrating under reduced pressure, separating and purifying by a silica gel column, and concentrating to obtain an off-white product;
step (g): preparation of 10-chloro-5-hydroxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazolin-10 (9H) -one
Dissolving a compound 5-methoxy-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline-10 (9H) -ketone in dichloromethane, slowly dropwise adding aluminum trichloride into the system, and reacting at room temperature for at least 12H; removing solvent by distillation, hydrolyzing the residue with sodium hydroxide solution, acidifying the obtained solution with hydrochloric acid, and extracting with ethyl acetate to obtain 10-chloro-5-hydroxy-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazolin-10 (9H) -one; the molar ratio of 5-methoxy-2, 3-dihydro- [1,4] dioxan [2,3-f ] quinazolin-10 (9H) -one to aluminum trichloride is 1: 3;
a step (h): preparation of dioxanoquinazoline derivatives
Dissolving 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazoline-5-alcohol in DMF, adding potassium carbonate, stirring at normal temperature for half an hour until the solution is completely dissolved, heating to 60-90 ℃, then dropwise adding R-X into the system, reacting for 6-8h, and detecting the reaction process by TlC. After the reaction is finished, pouring the reactant into 50mL of ice water, and performing suction filtration to obtain a series of dioxane quinazoline derivatives; r in R-X is the same as below, and X is halogen; preferably 1-2mmol of R-X per 1mmol of 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-ol;
r is straight-chain or branched alkane, nitrogen-substituted straight-chain alkane, alkoxy-substituted straight-chain or branched alkane, saturated cycloalkane-substituted straight-chain alkane, nitrogen-oxygen-containing saturated heterocyclic group-substituted straight-chain or branched alkane; if R is methyl, step (g) and step (h) may not be performed.
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| CN115433194A (en) * | 2022-09-13 | 2022-12-06 | 上海毕得医药科技股份有限公司 | Synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530063A (en) * | 2015-01-13 | 2015-04-22 | 北京达立泰制药科技有限公司 | Quinazoline and heterocyclic ring compounds, preparing method of compounds, and application of compounds serving as epidermal growth factor receptor inhibitors used for treating cancer |
| CN108503650A (en) * | 2017-02-27 | 2018-09-07 | 北京赛特明强医药科技有限公司 | Dioxane and quinazoline compounds or its pharmaceutical salts or its hydrate and its application as tyrosine kinase inhibitor |
| CN109776551A (en) * | 2019-03-05 | 2019-05-21 | 北京工业大学 | Dioxanes and quinazoline derivant preparation method |
-
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- 2021-02-02 CN CN202110150594.4A patent/CN112939995A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530063A (en) * | 2015-01-13 | 2015-04-22 | 北京达立泰制药科技有限公司 | Quinazoline and heterocyclic ring compounds, preparing method of compounds, and application of compounds serving as epidermal growth factor receptor inhibitors used for treating cancer |
| CN108503650A (en) * | 2017-02-27 | 2018-09-07 | 北京赛特明强医药科技有限公司 | Dioxane and quinazoline compounds or its pharmaceutical salts or its hydrate and its application as tyrosine kinase inhibitor |
| CN109776551A (en) * | 2019-03-05 | 2019-05-21 | 北京工业大学 | Dioxanes and quinazoline derivant preparation method |
Non-Patent Citations (1)
| Title |
|---|
| ALEXEY G. SERGEEV等: "Palladium-Catalyzed Hydroxylation of Aryl Halides under Ambient Conditions", 《ANGEW. CHEM. INT. ED.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115433194A (en) * | 2022-09-13 | 2022-12-06 | 上海毕得医药科技股份有限公司 | Synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative |
| CN115433194B (en) * | 2022-09-13 | 2023-06-23 | 上海毕得医药科技股份有限公司 | Synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative |
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