CN111217821B - Preparation method of series dioxane quinazoline derivatives - Google Patents
Preparation method of series dioxane quinazoline derivatives Download PDFInfo
- Publication number
- CN111217821B CN111217821B CN202010173501.5A CN202010173501A CN111217821B CN 111217821 B CN111217821 B CN 111217821B CN 202010173501 A CN202010173501 A CN 202010173501A CN 111217821 B CN111217821 B CN 111217821B
- Authority
- CN
- China
- Prior art keywords
- dihydro
- dioxo
- quinazolin
- reaction
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Series ofA preparation method of dioxane quinazoline derivatives, belonging to the field of synthesis of drug intermediates. The reaction condition of the route is mild, compared with the reported route, the steps are simpler, and the yield is higher. The R group is methyl, ethyl, propyl, isopropyl, methoxyethyl, ethoxypropyl, N-dimethylaminopropyl, tetrahydrofuran-3-oxyl, 1-methylpiperidine-4-methyl, 3-pyrrolidinopropyl, 3-cyclohexylpropoxy and N, 4-dimethylpiperidine-1-carboxamide.
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
As can be seen from the global cancer statistics data released annually by the International agency for research on cancer (IARC), the number of new cancer cases is over 1000 ten thousand per year, the number of deaths is about several million to ten million, and the global cancer burden is further increased. Also, the cancers with high morbidity and mortality every year include lung cancer, breast cancer, stomach cancer, and the like. In recent years, targeted therapy has achieved significant effects on the treatment of some tumors, and is a research hotspot in the field of cancer treatment at present. Targeted Therapy has resulted in significant efficacy in The Treatment of certain types of Cancer starting late 90 years, as effectively as chemotherapy, but with much reduced side effects compared to chemotherapy (Troy B. targeted Cancer Therapy: The Next Generation of Cancer Treatment [ J ]. Current Drug Discovery Technologies,2015,12(1): 3-20.). The principle of this Therapy is the use of small Molecules with abnormal or deregulated proteins specific for anticancer cells, which specifically block their binding to the kinase pocket in competition with ATP, blocking downstream Signaling pathways, and thus further inhibiting the proliferation and differentiation of tumor cells, a therapeutic approach at the cellular molecular level against well-defined oncogenic sites (which may be a protein molecule or a gene fragment inside tumor cells) (Ito, Fumiaki. formed Target Therapy for Cancer: Anti-Cancer Drugs Targeting Growth-Factor signalling Molecules [ J ]. Biological & Pharmaceutical Bulletin,2011, 34(12): 1773.). Corresponding therapeutic drugs can be designed, which when introduced into the body will specifically select oncogenic sites to act in combination, leading to specific tumor cell death without reaching normal tissue cells surrounding the tumor (Ammad F, Chih-Wen S, Hurng-Wern H, et al TRAIL, Wnt, Sonic Hedgehog, TGF β, and miRNA signalling Are electrode Targets for Oral Cancer Therapy [ J ]. International Journal of Molecular Sciences,2017,18(7): 1523.). Therefore, the research on the small molecular tyrosine kinase inhibitor for treating various tumors and cancers has great significance for the medical health industry of human beings.
Quinazoline compounds are substances with wide biological activity, and mainly show biological activities of cancer resistance, antibiosis, anti-inflammation, antimalarial, hypertension resistance and the like. This class of compounds, especially 4-anilinoquinazolines, is of interest because of their stable epidermal growth factor receptor kinase activity and high selectivity (Alkahtani H M, Abdalla A N, Obaidelah A J, et al Synthesis, cytoxic evaluation, and molecular binding students of novel quinazoline derivatives with benzazenesulfonamides and amide peptides: Dual inhibitors of EGFR/HER2[ J ]. Bioorganic chemistry, 201995: 103461.). In recent years, researchers have found many quinazoline derivatives with good biological activity, some of which have been developed as drugs. Currently, the quinazoline small-molecule drugs mainly include Gefitinib (Gefitinib), Erlotinib (Erlotinib), Afatinib (Afatinib), Lapatinib (Lapatinib), Icotinib (Icotinib), vandetanib (Vandetani), Prazosin hydrochloride (Prazosin chlorohydrate), proquinone (Proquazone), and Febrifugine (Febrifugine). Gefitinib and Erlotinib have good tyrosine kinase inhibitory activity, are approved for treating tumors associated with EGFR overexpression, have good clinical effects, but after more than 12 months of treatment, patients are found to have drug Resistance to the T790M mutation (Bartholomeusz C, Yamasaki F, Saso H, et al. Gemcitabine overcommens Erlotinib Resistance in EGFR-overexpression Cancer Cells through Down regulation of Akt [ J ]. Journal of Cancer,2011,2: 435 and 442.). The irreversible tyrosine kinase inhibitor Afatinib (Afatinib) was once considered to be an effective drug against the T790M mutation due to its higher kinase inhibitory activity in vitro against the T790M mutation than gefitinib or erlotinib, but the drug was found to have a treatment rate of less than 10% after entering clinical experimental phase (Liao B C, Lin C, Yang C H, et al. novel EGFR Inhibitors in Non-small Cell Lung Cancer: Current Status of Afatinib [ J ]. Current Oncology Reports,2017, 19(1): 4.). Lapatinib also has the characteristics of the drugs, but the lapatinib is not completely absorbed by oral administration and is easy to generate drug resistance and the like.
The synthesis method of quinazoline compounds is becoming more mature. Generally, a quinazoline nucleus is constructed by a cyclization reaction, and then a substitution reaction with a different substituent or the like is performed. Moreover, researches show that constructing a dioxane at the 5 and 6 positions of the quinazoline parent nucleus has a great effect on the biological activity of small molecules. The 2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline derivatives are drug intermediates with good activity, and the research on the synthetic method is significant work. The reported synthetic routes are as follows:
disclosure of Invention
The invention provides a synthetic route of 2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline derivatives as pharmaceutical intermediates. The method uses commercially available reagents and conventional reaction conditions, and has the advantages of simple steps and mild reaction conditions.
A method for synthesizing a 10-chloro-5-substituent-2, 3-dihydro- [1,4] dioxane [2,3-f ] quinazoline derivative, comprising the steps of:
step (a): preparation of 6-amino-2, 3-dihydroxybenzoic acid
Adding a commercially available compound 6-amino-2, 3-dimethoxybenzoic acid methyl ester serving as a raw material into a round-bottom flask filled with anhydrous dichloromethane, stirring until the methyl ester is completely dissolved, and adding iodotrimethylsilane in batches at 40-50 ℃; the reaction was refluxed for at least 20 hours, cooled to room temperature and MeOH (5ml) was added to the reaction mixture to remove excess silane; rotary evaporating, extracting with water and ethyl acetate, and drying the organic phase to obtain 6-amino-2, 3-dihydroxybenzoic acid; wherein the mol ratio of the iodotrimethylsilane to the methyl 6-amino-2, 3-dimethoxybenzoate is preferably 6.5: 1;
step (b): preparation of 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid
Dissolving 6-amino-2, 3-dihydroxybenzoic acid in DMF, adding potassium carbonate, stirring at normal temperature for half an hour, dropwise adding 1, 2-dibromoethane into the system, heating to 60 ℃, detecting the reaction process by TLC, pouring the mixed solution into ice water after the reaction is finished, separating out solids, and performing suction filtration to obtain a compound 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid; at least 3mmol of potassium carbonate per 1mmol of 6-amino-2, 3-dihydroxybenzoic acid, 0.12ml of 1, 2-dibromoethane;
step (c): preparation of 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one
Adding a compound 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid into a round-bottom flask filled with absolute ethyl alcohol, stirring until the compound is completely dissolved, and adding formamidine acetate in batches at the temperature of 60-100 ℃; carrying out cyclization reaction for at least 5 hours, and cooling to room temperature; adding ethanol, stirring, filtering to obtain solid, washing with ethanol, and drying to obtain 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one; wherein the molar ratio of formamidine acetate to 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid is preferably 1.2: 1;
step (d): preparation of 5-bromo-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one
Dissolving 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -ketone in dry carbon tetrachloride, heating and stirring to completely dissolve, adding NBS and AIBN reagents in batches, and reacting at 80 ℃ for 4-6 hours; the progress of the reaction was checked by thin layer chromatography. After the reaction is finished, cooling, rotary evaporating, extracting by using water and dichloromethane, and drying an organic phase to obtain 5-bromo-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one; at least 1.05mmol NBS per 1mmol 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one, 0.1mmol AIBN;
a step (e): preparation of 5-hydroxy-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (7H) -one
Dissolving 5-bromo-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one in tetrahydrofuran solution, stirring for 10 min until the solution is completely dissolved, adding saturated aqueous sodium hydroxide solution into the mixture under ice bath, reacting at 0 ℃ for at least 1 hour, and detecting the reaction process by thin layer chromatography. At the end of the reaction, rotary evaporation is carried out, water and dichloromethane are used for extraction, and the organic phase is dried; obtaining pure 5-hydroxy-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (7H) -one;
step (f): preparation of 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-ol
Adding thionyl chloride into the 5-hydroxy-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (7H) -one compound for dissolving, heating, carrying out reflux reaction for 4-6H, and detecting the reaction process by TLC. After the reaction is finished, removing thionyl chloride by rotary evaporation; dissolving the obtained solid in dichloromethane, and separating and purifying by silica gel column to obtain pure 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-ol;
step (g): 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. For example, R is methyl, ethyl, propyl, isopropyl, methoxyethyl, ethoxypropyl, N-dimethylaminopropyl, tetrahydrofuran-3-oxyl, 1-methylpiperidine-4-methyl, 3-pyrrolidinopropyl, 3-cyclohexylpropoxy, N, 4-dimethylpiperidine-1-carboxamido.
Reaction conditions are as follows: (a) DCM, Iodotrimethylsilane, at 40-50 ℃ for 20 h; (b) DMF, K2CO3, 1,2-Dibromoethane,60℃；(c)EtOH,Formamidine acetate,60-100℃；(d)CCl4,NBS, AIBN,80℃,4-6h；(e)THF,NaOH,0℃,1h；(f)SOCl2,80℃,4-6h；(g)DMF, K2CO3,R-X,60-90℃,6-8h。
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
Preparation of 5-chloro-N4- (3-chloro-2-fluorophenyl) quinazoline-4, 6-diamine (VIII-1)
Step (a): preparation of 6-amino-2, 3-dihydroxybenzoic acid
The commercially available compound methyl 6-amino-2, 3-dimethoxybenzoate (1.0g,4.74mmol) was added to a round-bottomed flask containing anhydrous dichloromethane (20ml), stirred until completely dissolved, and iodotrimethylsilane (4.2ml,30.9mmol) was added in portions at 50 ℃. The reaction was refluxed for 20 hours, cooled to room temperature and MeOH (10ml) was added to the reaction mixture to remove excess silane. Rotary evaporating, extracting with water and ethyl acetate, and drying organic phase to obtain 0.75g of compound 6-amino-2, 3-dihydroxybenzoic acid; white solid, yield: 75 percent.1H NMR(CDCl3,400MHz):δ19.63(s,1H),12.75(s,1H),9.08(s,1H), 6.83(d,1H),6.40(d,1H),6.17(s,2H).MS:170(M+H)+.
Step (b): preparation of 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid
Dissolving 6-amino-2, 3-dihydroxybenzoic acid (338mg,2.0mmol) in DMF (20ml), adding potassium carbonate (1.1g,8mmol), stirring at normal temperature for half an hour, dropwise adding 1, 2-dibromoethane (0.258ml,2.98 mmol) into the system, heating to 60 deg.C, detecting the reaction progress by TLC, after the reaction is finished, pouring the mixed solution into ice water, precipitating solid, and vacuum filtering to obtain the compound 6-amino-2, 3-dihydroxybenzo [ b ] b][1,4]280 mg of dioxa-5-carboxylic acid; white solid, yield: 82 percent.1H NMR(CDCl3,400MHz):δ12.75(s,1H),6.96(d, 1H),6.23(d,1H),6.07(s,1H),4.28(s,4H).MS:170(M+H)+.
Step (c): preparation of 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one
Reacting the compound 6-amino-2, 3-dihydroxybenzo [ b ]][1,4]Dioxa-5-carboxylic acid (1.13g,5.8mmol) was added to absolute ethanol (50 ml)) To a round bottom flask, stirred to complete dissolution and formamidine acetate (730mg,7mmol) was added portionwise at 80 ℃. After cyclization for 5 hours, the mixture was cooled to room temperature. Adding ethanol, stirring, vacuum filtering to obtain solid, washing with ethanol, and drying to obtain 2, 3-dihydro- [1,4] compound]Dioxo [2, 3-f)]1.05g of quinazolin-10 (9H) -one; white solid, yield: 93 percent.1H NMR(CDCl3,400MHz):δ12.24 (s,1H),9.03(s,1H),7.12(d,1H),7.00(d,1H),4.28(s,4H).MS:205(M+H)+.
Step (d): preparation of 5-bromo-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one
Taking 2, 3-dihydro- [1,4]Dioxo [2, 3-f)]Quinazolin-10 (9H) -one (500mg,2.5mmol) was dissolved in dry carbon tetrachloride (20ml), heated with stirring to dissolve completely, and NBS (467mg,2.625 mmol) and AIBN (41mg,0.25mmol) were added in portions and reacted at 80 ℃ for 6 hours. The progress of the reaction was checked by thin layer chromatography. After the reaction is finished, cooling, rotary evaporating, extracting by water and dichloromethane, and drying the organic phase to obtain the 5-bromo-2, 3-dihydro- [1, 4-]Dioxo [2, 3-f)]390mg of quinazolin-10 (9H) -one; white solid, yield: 78 percent.1H NMR(CDCl3,400MHz):δ12.24(s,1H),9.03(s,1H),7.08(s,1H),4.28(s, 4H).MS:283(M+H)+.
A step (e): preparation of 5-hydroxy-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (7H) -one
Reacting 5-bromo-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Quinazolin-10 (9H) -one (500mg,1.77mmol) was dissolved in tetrahydrofuran (20ml), stirred for 10 minutes until completely dissolved, and then saturated aqueous sodium hydroxide (104mg,2.6mmol) was added to the mixture under ice bath, reacted at 0 ℃ for 1 hour, and the progress of the reaction was checked by thin layer chromatography. At the end of the reaction, rotary evaporation was carried out and extraction was carried out with water and dichloromethane,the organic phase is dried. Obtaining the pure 5-hydroxy-2, 3-dihydro- [1,4]]Dioxo [2, 3-f)]Quinazolin-10 (7H) -one 360 mg; white solid, yield: 72 percent.1H NMR(CDCl3,400MHz):δ11.60(s,1H),9.08(s,1H),8.50(s,1H), 6.06(s,1H),4.28(s,4H).MS:221(M+H)+.
Step (f): preparation of 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-ol
To 5-hydroxy-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Adding thionyl chloride into a quinazoline-10 (7H) -ketone (500mg,2.3mmol) compound for dissolving, heating, carrying out reflux reaction for 6H, and detecting the reaction progress by TLC. After the reaction is finished, removing thionyl chloride by rotary evaporation; dissolving the obtained solid in dichloromethane, and separating and purifying with silica gel column to obtain pure 10-chloro-2, 3-dihydro- [1,4]]Dioxo [2, 3-f)]295mg of quinazolin-5-ol; white solid, yield: 59 percent.1H NMR(CDCl3,400MHz):δ9.86(s,1H),9.50(s,1H),7.06(s,1H),4.28(s, 4H).MS:239(M+H)+.
Step (g): preparation of 5-chloro-N4- (3-chloro-2-fluorophenyl) quinazoline-4, 6-diamine
Reacting 10-chloro-2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]Quinazoline-5-ol (500mg,2.1mmol) is dissolved in DMF (20ml), potassium carbonate (580mg,4.2mmol) is added, stirring is carried out for half an hour at normal temperature until complete dissolution is achieved, heating is carried out to 90 ℃, methyl iodide (196 mu l,3.15mmol) is then dropwise added into the system, reaction is carried out for 8h, and the progress of the reaction is detected by TLC. After the reaction is finished, pouring the reactant into 50ml of ice water, and performing suction filtration to obtain 380mg of 5-chloro-N4- (3-chloro-2-fluorophenyl) quinazoline-4, 6-diamine; white solid, yield: 76 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)+.
Example 2
Preparation of 10-chloro-5-ethoxy-2, 3-dihydro- [1,4] dioxy [2,3-f ] quinazoline (VIII-2)
Steps (a) - (f) are the same as in example 1
Step (g): 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)]Quinazoline-5-ol (500mg,2.1mmol) is dissolved in DMF (20ml), potassium carbonate (580mg,4.2mmol) is added, stirring is carried out for half an hour at normal temperature until complete dissolution is achieved, heating is carried out to 90 ℃, bromoethane (107 mu l,3.35mmol) is dropwise added into the system, reaction is carried out for 8h, and the progress of the reaction is detected by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered to obtain 10-chloro-5-ethoxy-2, 3-dihydro- [1, 4%]Dioxy [2,3-f ]]440mg of quinazoline; white solid, yield: 88 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): 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-5-ol (500mg,2.1mmol) is dissolved in DMF (20ml), potassium carbonate (580mg,4.2mmol) is added, stirring is carried out for half an hour at normal temperature until complete dissolution is achieved, heating is carried out to 90 ℃, bromopropane (289 mu l,3.05mmol) is dropwise added into the system, reaction is carried out for 8h, and the progress of the reaction is detected by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered by suction to obtain 10-chloro-5-propoxy-2, 3-dihydro- [1, 4%]Dioxy [2,3-f ]]430mg of quinazoline; a white solid, a solid which is,yield: 86 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): 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 (500mg,2.1mmol) in DMF (20ml), adding potassium carbonate (580mg,4.2mmol), stirring at normal temperature for half an hour until complete dissolution, heating to 90 ℃, then dropwise adding 2-bromopropane (284 μ l,3.0mmol) into the system, reacting for 8h, and detecting the reaction progress by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered to obtain 10-chloro-5-isopropoxy-2, 3-dihydro- [1,4]]Dioxy [2,3-f ]]430mg of quinazoline; white solid, yield: 86 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): 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 quinazolin-5-ol (500mg,2.1mmol) in DMF (20ml), adding potassium carbonate (580mg,4.2mmol), stirring at room temperature for half an hour to dissolve completely, heatingTo 90 ℃, 1-chloro-2-methoxyethane (303mg,3.23mmol) was slowly added to the system, the reaction was carried out for 8h, and the progress of the reaction was checked by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered by suction to obtain 10-chloro-5- (2-methoxyethoxy) -2, 3-dihydro- [1, 4%]Dioxy [2,3-f ]]420mg of quinazoline; white solid, yield: 84 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): 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 (500mg,2.1mmol) in DMF (20ml), adding potassium carbonate (580mg,4.2mmol), stirring at room temperature for half an hour until completely dissolving, heating to 90 deg.C, slowly adding 1-chloro-3-ethoxypropane (412mg,3.35mmol) into the system, reacting for 8h, and detecting the reaction progress by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered by suction to obtain 10-chloro-5- (3-ethoxy propoxy) -2, 3-dihydro- [1, 4%]Dioxa [2,3-f]380mg of quinazoline; white solid, yield: 76 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): 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)]Quinazoline-5-ol (500mg,2.1mmol) is dissolved in DMF (20ml), potassium carbonate (580mg,4.2mmol) is added, stirring is carried out for half an hour at normal temperature until complete dissolution is achieved, heating is carried out to 90 ℃, then 3-chloro-1- (N, N-dimethyl) propylamine (411mg,3.4mmol) is slowly added into the system, reaction is carried out for 8h, and the progress of the reaction is detected by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered to obtain the 3- ((10-chloro-2, 3-dihydro- [1, 4)]Dioxo [2, 3-f)]Quinazolin-5-yl) oxy) -N, N-dimethylpropan-1-amine 400 mg; 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): 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 quinazolin-5-ol (500mg,2.1mmol) in DMF (20ml), adding potassium carbonate (580mg,4.2mmol), stirring at room temperature for half an hour until completely dissolved, heating to 90 deg.C, slowly adding 3-chlorotetrahydrofuran (378mg,3.55mmol) into the system, reacting for 8h, and detecting the reaction progress by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered to obtain 10-chloro-5- ((tetrahydrofuran-3-yl) oxy) -2, 3-dihydro- [1,4]Dioxy [2,3-f ]]370mg of quinazoline; white solid, yield: 74 percent.1H NMR(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): 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)]Quinazoline-5-ol (500mg,2.1mmol) was dissolved in DMF (20ml), potassium carbonate (580mg,4.2mmol) was added, stirred at room temperature for half an hour until complete dissolution, heated to 90 ℃ and then 4- (chloromethyl) -1-methylpiperidine (521mg,3.55mmol) was slowly added to the system, reacted for 8h, and the progress of the reaction was checked by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered to obtain 10-chloro-5- ((1-methylpiperidin-4-yl) methoxy) -2, 3-dihydro- [1, 4%]Dioxa [2,3-f]290mg of quinazoline; white solid, yield: 58 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): 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 (500mg,2.1mmol) in DMF (20ml), adding potassium carbonate (580mg,4.2mmol), stirring at room temperature for half an hour to completionDissolving, heating to 90 ℃, then slowly adding 1- (3-chloropropyl) pyrrolidine (536mg,3.65mmol) into the system, reacting for 8h, and detecting the reaction progress by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered by suction to obtain 10-chloro-5- (3- (pyrrolidine-1-yl) propoxy) -2, 3-dihydro- [1, 4%]Dioxo [2, 3-f)]320mg of quinazoline; white solid, yield: and 64 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): 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 quinazolin-5-ol (500mg,2.1mmol) in DMF (20ml), adding potassium carbonate (580mg,4.2mmol), stirring at room temperature for half an hour until completely dissolved, heating to 90 deg.C, slowly adding (3-chloropropyl) cyclohexane (584mg,3.65mmol) into the system, reacting for 8h, and detecting the reaction progress by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered by suction to obtain 10-chloro-5- (3-cyclohexylpropoxy) -2, 3-dihydro- [1, 4%]Dioxa [2,3-f]350mg of 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 4- ((10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-yl) oxy) methyl) -N-methylpiperidine-1-carboxamide (VIII-12)
Steps (a) - (f) are the same as in example 1
Step (g): 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)]Quinazoline-5-ol (500mg,2.1mmol) was dissolved in DMF (20ml), potassium carbonate (580mg,4.2mmol) was added, stirred at room temperature for half an hour until complete dissolution, heated to 90 ℃ and then 4- (chloromethyl) -N-methylpiperidine-1-carboxamide (665mg,3.5 mmol) was slowly added to the system, reacted for 8h and the progress of the reaction was checked by TLC. After the reaction is finished, the reactant is poured into 50ml of ice water and filtered to obtain 4- ((10-chloro-2, 3-dihydro- [1, 4)]Dioxo [2, 3-f)]Quinazolin-5-yl) oxy) methyl) -N-methylpiperidine-1-carboxamide 270 mg; white solid, yield: 54 percent.1H NMR(CDCl3,400MHz): δ9.53(s,1H),7.66(s,1H),7.21(s,1H),4.28(s,4H),4.10(d,2H),3.54(m,4H), 2.75(s,3H),2.01(m,1H),1.52(m,4H).MS:393(M+H)+.
Claims (4)
1. A method for synthesizing a dioxanoquinazoline derivative, which comprises the steps of:
step (a): preparation of 6-amino-2, 3-dihydroxybenzoic acid
Adding a commercially available compound 6-amino-2, 3-dimethoxybenzoic acid methyl ester serving as a raw material into a round-bottom flask filled with anhydrous dichloromethane, stirring until the methyl ester is completely dissolved, and adding iodotrimethylsilane in batches at 40-50 ℃; refluxing the reaction for at least 20 hours, cooling to room temperature, and adding MeOH to the reaction mixture to remove excess silane; rotary evaporating, extracting with water and ethyl acetate, and drying organic phase to obtain 6-amino-2, 3-dihydroxybenzoic acid; wherein the molar ratio of the iodotrimethylsilane to the methyl 6-amino-2, 3-dimethoxybenzoate is 6.5: 1;
step (b): preparation of 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid
Dissolving 6-amino-2, 3-dihydroxybenzoic acid in DMF, adding potassium carbonate, stirring at normal temperature for half an hour, dropwise adding 1, 2-dibromoethane into the system, heating to 60 ℃, detecting the reaction process by TLC, pouring the mixed solution into ice water after the reaction is finished, separating out solid, and performing suction filtration to obtain a compound 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid; at least 3mmol of potassium carbonate per 1mmol of 6-amino-2, 3-dihydroxybenzoic acid, 0.12ml of 1, 2-dibromoethane;
step (c): preparation of 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one
Adding the compound 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid into a round-bottomed flask filled with absolute ethyl alcohol, stirring until the compound is completely dissolved, and adding formamidine acetate in batches at the temperature of 60-100 ℃; carrying out cyclization reaction for at least 5 hours, and cooling to room temperature; adding ethanol, stirring, filtering to obtain solid, washing with ethanol, and drying to obtain 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one; wherein the molar ratio of formamidine acetate to 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid is 1.2: 1;
step (d): preparation of 5-bromo-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one
Dissolving 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one in dry carbon tetrachloride, heating and stirring to completely dissolve, adding NBS and AIBN reagents in batches, reacting at 80 ℃ for 4-6 hours, and detecting the reaction process by thin layer chromatography; after the reaction is finished, cooling, rotary evaporating, extracting by using water and dichloromethane, and drying an organic phase to obtain 5-bromo-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one; at least 1.05 mmoleNBS, 0.1 mmoleAIBN per 1mmol of 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one;
a step (e): preparation of 5-hydroxy-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (7H) -one
Dissolving 5-bromo-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one in tetrahydrofuran solution, stirring for 10 min until the solution is completely dissolved, adding saturated aqueous sodium hydroxide solution into the mixture under ice bath, reacting at 0 ℃ for at least 1 hour, and detecting the reaction process by thin layer chromatography; when the reaction is finished, performing rotary evaporation, extracting with water and dichloromethane, and drying the organic phase to obtain a pure product of 5-hydroxy-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (7H) -one;
step (f): preparation of 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-ol
Adding thionyl chloride into the 5-hydroxy-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (7H) -one compound for dissolving, heating, carrying out reflux reaction for 4-6H, and detecting the reaction process by TLC; after the reaction is finished, removing thionyl chloride by rotary evaporation; dissolving the obtained solid in dichloromethane, and separating and purifying by silica gel column to obtain pure 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-ol;
step (g): 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 mixture is completely dissolved, heating to 60-90 ℃, then dropwise adding R-X into the system, reacting for 6-8h, detecting the reaction process by TLC, after the reaction is finished, pouring the reactant into 50ml of ice water, and carrying out suction filtration to obtain a series of dioxane quinazoline derivatives; r in R-X is the same as below, and X is halogen; 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, N-dimethylaminopropyl, tetrahydrofuran-3-oxyl, 1-methylpiperidine-4-methyl, 3-cyclohexylpropoxy and N, 4-dimethylpiperidine-1-formamide.
2. A process for the synthesis of a dioxanoquinazoline derivative according to claim 1, wherein the straight or branched chain alkane is selected from methyl, ethyl, propyl, isopropyl, and the alkoxy-substituted straight or branched chain alkane is selected from methoxyethyl, ethoxypropyl.
3. The method for synthesizing a dioxanoquinazoline derivative according to claim 1, wherein the linear or branched alkane substituted with the nitrogen-oxygen-containing saturated heterocyclic group is 3-pyrrolidinopropyl.
4. A method for synthesizing a dioxanoquinazoline derivative according to claim 1, wherein:
step (b): at least 3mmol of potassium carbonate per 1mmol of 6-amino-2, 3-dihydroxybenzoic acid, 0.12ml of 1, 2-dibromoethane;
step (c): wherein the molar ratio of formamidine acetate to 6-amino-2, 3-dihydroxybenzo [ b ] [1,4] dioxa-5-carboxylic acid is 1.2: 1;
step (d): at least 1.05 mmoleNBS, 0.1 mmoleAIBN per 1mmol of 2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-10 (9H) -one;
step (g): 1-2mmol of R-X per 1mmol of 10-chloro-2, 3-dihydro- [1,4] dioxo [2,3-f ] quinazolin-5-ol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010173501.5A CN111217821B (en) | 2020-03-13 | 2020-03-13 | Preparation method of series dioxane quinazoline derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010173501.5A CN111217821B (en) | 2020-03-13 | 2020-03-13 | Preparation method of series dioxane quinazoline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111217821A CN111217821A (en) | 2020-06-02 |
| CN111217821B true CN111217821B (en) | 2021-04-23 |
Family
ID=70830040
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010173501.5A Active CN111217821B (en) | 2020-03-13 | 2020-03-13 | Preparation method of series dioxane quinazoline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111217821B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905335A (en) * | 2017-03-03 | 2017-06-30 | 北京工业大学 | Quinazo heterocycle compound and its preparation method and application |
| WO2018153293A1 (en) * | 2017-02-27 | 2018-08-30 | 北京赛特明强医药科技有限公司 | Dioxanoquinazoline, dioxanoquinazoline-type compound, preparation method therefor and use thereof |
| CN109776551A (en) * | 2019-03-05 | 2019-05-21 | 北京工业大学 | Dioxanes and quinazoline derivant preparation method |
-
2020
- 2020-03-13 CN CN202010173501.5A patent/CN111217821B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018153293A1 (en) * | 2017-02-27 | 2018-08-30 | 北京赛特明强医药科技有限公司 | Dioxanoquinazoline, dioxanoquinazoline-type compound, preparation method therefor and use thereof |
| CN106905335A (en) * | 2017-03-03 | 2017-06-30 | 北京工业大学 | Quinazo heterocycle compound and its preparation method and application |
| 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 |
|---|
| Discovery of Dioxino[2,3-f]quinazoline derivative VEGFR-2 inhibitors exerting significant antipro-liferative activity in HUVECs and mice;H. Fan et al.;《European Journal of Medicinal Chemistry》;20190417;第349-356页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111217821A (en) | 2020-06-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2269994B1 (en) | The polymorphs of 4-anilinoquinazoline derivatives, the preparation methods and uses thereof | |
| CN107540661A (en) | Crystallization as the Aniline pyrimidine compound of EGFR inhibitor | |
| CN107573327B (en) | Indazole-formamide-pyridone derivative and preparation method and application thereof | |
| CN110283162B (en) | Epidermal growth factor receptor inhibitor and application thereof | |
| CN112300082B (en) | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application | |
| CN106946868B (en) | Nitric oxide donator type coumarin derivative, preparation method and medical usage | |
| CN104557913A (en) | Pyridopyrimidine compounds as well as preparation method and application thereof | |
| CN110590681B (en) | Novel quinazoline ketone compound and preparation method and application thereof | |
| CN111217821B (en) | Preparation method of series dioxane quinazoline derivatives | |
| CN109776551B (en) | Process for preparing dioxanoquinazoline derivatives | |
| CN115368306B (en) | HDAC inhibitor containing tetrahydroisoquinoline structure, composition and application thereof | |
| CN111675647B (en) | 2-indolone PAK1 inhibitor and application thereof in antitumor drugs | |
| CN116284018A (en) | Preparation method and application of furo [2,3-b ] quinoline derivative | |
| CN107501283B (en) | Preparation of substituted arylmethyl hetero-substituted anilino ethylene glycol ether cycloquinazoline and application of tumor treatment drug | |
| CN109438279B (en) | Small molecule compound for overcoming EGFR drug-resistant mutation and preparation method and application thereof | |
| CN112939995A (en) | Process for preparing dioxanoquinazoline derivatives | |
| CN117865886B (en) | N- (quinoline-8-yl) quinoline-8-sulfonamide compound and application thereof | |
| CN1931869B (en) | Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use | |
| CN101003513A (en) | Compound in quinazoline class or its pharmaceutical salt preparation method, and medical usage | |
| CN115417877B (en) | Histone deacetylase inhibitor and preparation and application thereof in preparation of anti-cancer drugs | |
| CN112209875B (en) | 6-amino-4- (4-phenoxyphenethylamino) quinazoline derivative and preparation method and application thereof | |
| CN112010789A (en) | Vinyl sulfonamide or vinyl amide compounds, and preparation method and application thereof | |
| CN113956240B (en) | Pyrimidine derivatives and application thereof in preparing antitumor drugs | |
| CN103601722B (en) | New antitumoral compounds | |
| CN117126164B (en) | Pyrrolotriazines compound, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |