CN103242244B - Canertinib preparation method - Google Patents
Canertinib preparation method Download PDFInfo
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- CN103242244B CN103242244B CN201310180647.2A CN201310180647A CN103242244B CN 103242244 B CN103242244 B CN 103242244B CN 201310180647 A CN201310180647 A CN 201310180647A CN 103242244 B CN103242244 B CN 103242244B
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- morpholinyl
- dihydroquinazoline
- ketone
- propoxyl group
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000005461 Canertinib Substances 0.000 title abstract description 4
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 title abstract description 4
- 229950002826 canertinib Drugs 0.000 title abstract description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 5
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000005917 acylation reaction Methods 0.000 claims abstract description 4
- 238000006266 etherification reaction Methods 0.000 claims abstract description 4
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 claims abstract 2
- -1 chloro-4-fluoroanilino Chemical group 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000006482 condensation reaction Methods 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 3
- MPBUCOHXXNOLAZ-UHFFFAOYSA-N 3-chloro-n-fluoroaniline Chemical compound FNC1=CC=CC(Cl)=C1 MPBUCOHXXNOLAZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 3
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- HZPUQEDBAYDSJH-UHFFFAOYSA-N 6-amino-7-(3-morpholin-4-ylpropoxy)-3H-quinazolin-4-one Chemical compound NC=1C=C2C(NC=NC2=CC1OCCCN1CCOCC1)=O HZPUQEDBAYDSJH-UHFFFAOYSA-N 0.000 abstract 3
- JQNPQLKZPZFJCN-UHFFFAOYSA-N N-[7-(3-morpholin-4-ylpropoxy)-4-oxo-3H-quinazolin-6-yl]prop-2-enamide Chemical compound N1(CCOCC1)CCCOC1=C(C=C2C(NC=NC2=C1)=O)NC(C=C)=O JQNPQLKZPZFJCN-UHFFFAOYSA-N 0.000 abstract 3
- AEKHMWHEDFXEPV-UHFFFAOYSA-N 6-amino-7-hydroxy-1h-quinazolin-4-one Chemical compound N1C=NC(=O)C2=C1C=C(O)C(N)=C2 AEKHMWHEDFXEPV-UHFFFAOYSA-N 0.000 abstract 2
- VZKSLWJLGAGPIU-UHFFFAOYSA-N 3-morpholin-4-ylpropan-1-ol Chemical compound OCCCN1CCOCC1 VZKSLWJLGAGPIU-UHFFFAOYSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- 230000006837 decompression Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- ANGDBPOEJIYLPR-UHFFFAOYSA-N n-chloro-3-fluoroaniline Chemical compound FC1=CC=CC(NCl)=C1 ANGDBPOEJIYLPR-UHFFFAOYSA-N 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- 239000005785 Fluquinconazole Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical group C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a Canertinib (I) preparation method which comprises the following steps: performing etherification reaction on 6-amino-7-hydroxy-3,4-dihydroquinazoline-4-one (II) and 3-(4-morpholinyl)-1-propanol to generate 6-amino-7-[3-(4-morpholinyl)propoxy]-3,4-dihydroquinazoline-4-one (III); performing acylation reaction on the compound (III) and propenoic acid or acryloyl chloride to generate 7-[3-(4-morpholinyl)propoxy]-6-acrylamido-3,4-dihydroquinazoline-4-one (IV); and performing condensation on the compound (IV) and 4-fluoro-3-chloroaniline to obtain Canertinib (I). The preparation method is simple, economic and environment-friendly in process, and meets the requirements for large-scale industrialization.
Description
Patent of the present invention other its name of submitting on the same day of REFERENCE TO RELATED people can be called the application for a patent for invention of " 6-amino-7-hydroxyl-3,4-dihydroquinazoline-4-ketone ".
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of card is how for the preparation method of Buddhist nun.
Background technology
How card is for Buddhist nun (Canertinib, I), chemistry 4-(the chloro-4-fluoroanilino of 3-)-7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido quinazoline by name, it is the irreversible EGF-R ELISA of one (pan-ErbB) selective depressant by Pfizer Inc. and Warner Lambert AG Safnern cooperative research and development, it can be attached to the atriphos binding site on ErbB family all member cells's films surface, thus suppresses activation and the downstream mitosis signal transduction pathway thereof of these acceptors.Clinical research shows that this product has good tolerance, can effectively treat the kinds of tumors such as recurrent metastatic breast cancer in its, oophoroma, cervical carcinoma, all can show synergy with multiple antineoplastic coupling.
No. CN1160338Cth, Chinese patent, No. CN1438994A and No. CN1745073A report card how for the preparation method of Buddhist nun: with parent nucleus 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-nitro-7-Fluquinconazole quinoline (VIII) for initiation material, there is the substitution reaction of 7-position with 3-(4-morpholinyl)-1-propyl alcohol under alkali condition, generate 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-nitro-7-[3-(4-morpholinyl)-1-propoxyl group] quinazoline (IX); Intermediate (IX) nitroreduction through 6-position, obtains corresponding amino-compound (X); How amino-compound (X) and acrylic acid or acryloyl chloride generation acylation reaction obtain card for Buddhist nun (I).
In addition, " Shandong medicine thing " 30 volumes the 10th phase in 2011 the 559th page and " Chinese Journal of Pharmaceuticals " 41 volumes the 6th phase in 2010 the 404th page also report improving one's methods to above-mentioned preparation, and have studied the method preparing intermediate (VIII) from 7-Fluquinconazole quinoline-3-ketone (V) through reactions such as nitrated, chloro and condensations.
Find out thus, the at present preparation of card how for Buddhist nun mainly carries out 4-position respectively by intermediate (VII), the sense of 6-position and 7-position is converted realizes.Because intermediate (VII) is fluorochemical, raw material not easily obtains, and step is more, and many steps need to carry out abstraction and purification by column chromatography, are thus not suitable for industrialized requirement.
Summary of the invention
The object of the invention is to seek new prepare approach, according to the Atom economy synthesis theory of Green Chemistry, a kind of card of improvement is provided how to replace the preparation method of Buddhist nun, its raw material is easy to get, concise in technology, economic environmental protection, is conducive to the suitability for industrialized production of this medicine, promotes the development of the economic technology of this bulk drug.
To achieve these goals, main technical schemes provided by the present invention is as follows: how a kind of card is for Buddhist nun's (4-(the chloro-4-fluoroanilino of 3-)-7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido quinazoline, I) preparation method
It is characterized in that described preparation method comprises the steps: 6-amino-7-hydroxyl-3, 4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3, 4-dihydroquinazoline-4-ketone (III), this compound (III) carries out acylation reaction with acrylic acid or acryloyl chloride and generates 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3, 4-dihydroquinazoline-4-ketone (IV), this compound (IV) and the fluoro-3-chloroaniline of 4-carry out condensation reaction obtained the card and how to replace Buddhist nun (I).
In addition, the present invention also provides following attached technical scheme:
Raw material 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3, the 4-dihydroquinazoline-4-ketone (IV) of described condensation reaction and the molar ratio of the fluoro-3-chloroaniline of 4-are 1: 1-2, preferably 1: 1.1-1.4.
The condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N, N '-DIC (DIC), 1-hydroxyl-BTA (HOBt), O-BTA-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester (TBTU), O-(7-azo BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), preferred BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).
The alkali promoter of described condensation reaction is triethylamine (TEA), pyridine, 2, 6-lutidines, DMAP (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN), 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 4-diazabicylo [2.2.2] octane (DABCO), preferably 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN) or 1, 4-diazabicylo [2.2.2] octane (DABCO).
The solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, methyl-sulfoxide, DMF or acetonitrile, preferred acetonitrile.
Described condensation reaction, is characterized in that the temperature of described reaction is 0-120 DEG C, preferred 50-60 DEG C.
Compared to prior art, how card involved in the present invention replaces the preparation method of Buddhist nun, it is by 6-amino-7-hydroxyl-3, 4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3, 4-dihydroquinazoline-4-ketone (III), this compound (III) can obtain target product by acidylate and condensation reaction again, so advantage of the present invention mainly raw material is easy to get, concise in technology, economic environmental protection, be conducive to the suitability for industrialized production of this medicine, promote the development of the economic technology of this bulk drug.
Detailed description of the invention
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
Embodiment one:
Under room temperature, in there-necked flask, add diisopropyl azo-2-carboxylic acid (3mL, 15mmol) and oxolane 5mL, under room temperature, drip the oxolane 25mL solution of triphenylphosphine (4.0g, 15mmol), keep room temperature reaction 2 hours.Under nitrogen protection; by 3-(4-morpholinyl)-1-propyl alcohol (0.49g; oxolane 5mL dropwise 3.4mmol) joins in above-mentioned reaction system; drip standby after; add 6-amino-7-hydroxyl-3; 4-dihydroquinazoline-4-ketone (II) (0.53g, 3.0mmol), stirring at room temperature reacts 4 hours.Drip the oxolane 5mL solution of 3-(4-morpholinyl)-1-propyl alcohol (0.38g, 2.6mmol), continue room temperature reaction 2 hours, TLC monitoring reaction terminates.Vacuum distillation recovered solvent, residue watery hydrochloric acid adjusts pH=5-6, is extracted with ethyl acetate, and organic phase saturated sodium carbonate adjusts pH=10-11.Separate aqueous phase, vacuum freezedrying, obtain off-white color solid 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3,4-dihydroquinazoline-4-ketone (III) 0.80g, yield is 87.7%.
Embodiment two:
6-amino-7-[3-(4-morpholinyl) propoxyl group]-3 is added in there-necked flask, 4-dihydroquinazoline-4-ketone (III) (0.76g, 2.5mmol), triethylamine (0.25g, 2.5mmol) with carrene 20mL, be warming up to 40-45 DEG C, the system that is stirred to is dissolved homogeneous.Be down to less than 10 DEG C, slowly drip the carrene 10mL solution of acryloyl chloride (0.25g, 2.8mmol), drip off rear room temperature and continue reaction 6 hours, TLC detection reaction terminates.Reactant liquor uses 10% sodium bicarbonate solution and water washing respectively, anhydrous sodium sulfate drying.Decompression and solvent recovery, residue re-crystallizing in ethyl acetate, obtains white solid 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3,4-dihydroquinazoline-4-ketone (IV) 0.81g, yield 90.5%.
Embodiment three:
Under nitrogen protection; 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 100mL.Under stirring, drip 1,8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) (2.28g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 60 DEG C, continue reaction 12 hours.Decompression distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M NaOH 20mL.Separate organic phase, dry, reduced pressure concentration.Residue 100mL oxolane dissolves, and adds the chloro-3-fluoroaniline (1.89g, 13mmol) of 4-and sodium hydride (0.32g, 13mmol), is warming up to 50 DEG C, stirring reaction 5 hours, and TLC monitoring reaction terminates.With saturated aqueous common salt cancellation reaction, separate organic phase, dry, vacuum distillation recovered solvent, obtains pale solid.How obtain off-white color solid card for Buddhist nun (I) 4.05g with ethyl alcohol recrystallization, yield is 83.5%.
Embodiment four:
Under nitrogen protection; 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 100mL.Under stirring, drip 1,5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN) (1.86g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 60 DEG C, continue reaction 12 hours.Decompression distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M NaOH 20mL.Separate organic phase, dry, reduced pressure concentration.Residue 100mL oxolane dissolves, and adds the chloro-3-fluoroaniline (1.89g, 13mmol) of 4-and sodium hydride (0.32g, 13mmol), is warming up to 50 DEG C, stirring reaction 5 hours, and TLC monitoring reaction terminates.With saturated aqueous common salt cancellation reaction, separate organic phase, dry, vacuum distillation recovered solvent, obtains pale solid.How obtain off-white color solid card for Buddhist nun (I) 3.85g with ethyl alcohol recrystallization, yield is 79.4%.
Embodiment five:
Under nitrogen protection; 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g; 15mmol), the chloro-3-fluoroaniline of 4-(1.89g; 13mmol) with DMF 100mL.Under stirring, drip 1,8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) (2.28g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 60 DEG C, continue reaction 12 hours.Decompression distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M NaOH 20mL.Separate organic phase, dry, reduced pressure concentration.Residue from ethanol is recrystallized how off-white color solid card replaces Buddhist nun (I) 2.32g, and yield is 47.8%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to Spirit Essence of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (3)
1. how card replaces a Buddhist nun's preparation method, and how described card replaces the chemistry of Buddhist nun to be called 4-(the chloro-4-fluoroanilino of 3-)-7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido quinazoline (I)
It is characterized in that described preparation method comprises the steps: 6-amino-7-hydroxyl-3,4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3,4-dihydroquinazoline-4-ketone (III), described 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3,4-dihydroquinazoline-4-ketone (III) carries out acylation reaction with acrylic acid or acryloyl chloride and generates 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3,4-dihydroquinazoline-4-ketone (IV), described 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3,4-dihydroquinazoline-4-ketone (IV) and 4-fluoro-3-chloroaniline carry out condensation reaction and how obtain described card for Buddhist nun (I) under condensing agent and alkali promoter act on, raw material 7-[3-(4-morpholinyl) the propoxyl group]-6-acrylamido-3 of wherein said condensation reaction, the molar ratio of the fluoro-3-chloroaniline of 4-dihydroquinazoline-4-ketone (IV) and 4-is 1:1-2, the condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide, carbonyl dimidazoles, N, N '-DIC, 1-hydroxyl-BTA, O-BTA-N, N, N', N'-tetramethylurea tetrafluoro boric acid ester, O-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, BTA-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester or BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate, the alkali promoter of described condensation reaction is triethylamine, pyridine, 2,6-lutidines, DMAP, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [the 4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-ten one-7-alkene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane.
2. block the preparation method how replacing Buddhist nun according to claim 1, it is characterized in that: the solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, methyl-sulfoxide, DMF or acetonitrile.
3. block the preparation method how replacing Buddhist nun according to claim 1, it is characterized in that: the temperature of described condensation reaction is 0-120 DEG C.
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