CN108264476A - A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate - Google Patents
A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate Download PDFInfo
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- CN108264476A CN108264476A CN201810051599.XA CN201810051599A CN108264476A CN 108264476 A CN108264476 A CN 108264476A CN 201810051599 A CN201810051599 A CN 201810051599A CN 108264476 A CN108264476 A CN 108264476A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 23
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 23
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 229940049706 benzodiazepine Drugs 0.000 claims abstract description 41
- 238000006467 substitution reaction Methods 0.000 claims abstract description 16
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 15
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 13
- 238000006722 reduction reaction Methods 0.000 claims abstract description 13
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 8
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 8
- -1 methoxyl group Chemical group 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 23
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- 235000019441 ethanol Nutrition 0.000 claims description 9
- APYLNYCULQUSLG-UHFFFAOYSA-N 9h-carbazole-3-carbonitrile Chemical compound C1=CC=C2C3=CC(C#N)=CC=C3NC2=C1 APYLNYCULQUSLG-UHFFFAOYSA-N 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 230000002152 alkylating effect Effects 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000003863 metallic catalyst Substances 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 239000012320 chlorinating reagent Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000008236 heating water Substances 0.000 claims description 6
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- 229940071870 hydroiodic acid Drugs 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- FWIROFMBWVMWLB-UHFFFAOYSA-N 1-bromo-3-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC(Br)=C1 FWIROFMBWVMWLB-UHFFFAOYSA-N 0.000 claims description 4
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 claims description 4
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical group CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 150000003851 azoles Chemical class 0.000 claims description 4
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 4
- 229940005991 chloric acid Drugs 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical class CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- ROEOVWIEALGNLM-UHFFFAOYSA-N 5h-benzo[b]carbazole Chemical compound C1=CC=C2C=C3C4=CC=CC=C4NC3=CC2=C1 ROEOVWIEALGNLM-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Natural products CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 150000002576 ketones Chemical class 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 3
- 125000005605 benzo group Chemical group 0.000 abstract 2
- HZPARRYXFNMNAO-UHFFFAOYSA-N C1C2=C(C)C(C)=CC=C2C=CC1 Chemical compound C1C2=C(C)C(C)=CC=C2C=CC1 HZPARRYXFNMNAO-UHFFFAOYSA-N 0.000 abstract 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- QNLZIZAQLLYXTC-UHFFFAOYSA-N dimethylnaphthalene Natural products C1=CC=CC2=C(C)C(C)=CC=C21 QNLZIZAQLLYXTC-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- FYKBAHQGSLNQBX-UHFFFAOYSA-N C(C)C1=CC2=C(C(C=3NC4=CC=CC=C4C3O2)(C)C)C=C1O Chemical class C(C)C1=CC2=C(C(C=3NC4=CC=CC=C4C3O2)(C)C)C=C1O FYKBAHQGSLNQBX-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 1
- 229960001611 alectinib Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate, and the anticancer drug Ai Li replaces 6,11 dihydro 5H benzos [b] carbazole of Buddhist nun's intermediated chemistry 8 hydroxyl of entitled 9 ethyl, 6,6 dimethyl, 11 oxa-, 3 formonitrile HCN；The present invention provides one kind with 2 methoxyl group, 5 hydroxyl, 8 dimethyl 7, 8 dihydronaphthalene, 7 ketone is starting material through chlorination, oxidation reaction, substitution reaction, alkylated reaction, ring-closure reaction, substitution reaction, reduction reaction, cyanation obtains 9 ethyls 6, 6 dimethyl, 8 hydroxyl, 11 oxa- 6, 11 dihydro 5H benzos [b] carbazole, 3 formonitrile HCN, preparation process is succinct, raw material is easy to get, synthesis condition is simple, it is economic and environment-friendly, product yield is high with product purity, it is advantageously implemented industrialization, reduce manufacturing cost, suitable for producing in enormous quantities, the new anticancer drug Ai Li sought is meaningful for the economic technology of Buddhist nun for Ai Li for the preparation method of Buddhist nun's intermediate.
Description
Technical field
The present invention relates to the preparation methods that pharmaceutical technology field more particularly to a kind of anticancer drug Ai Li replace Buddhist nun's intermediate.
Background technology
Ai Li is by the Choongwae Pharmacutical Corp of Japan of branch company of Roche Holding Ag (Roche) for Buddhist nun (Alectinib)
A kind of new anaplastic lymphoma kinase (ALK) inhibitor of (Chugai Pharmaceutical) exploitation, for treating ALK bases
Because of the Patients with Non-small-cell Lung of rearrangement, since it replaces Buddhist nun (Crizotinib) drug resistant patient still effective, and energy gram azoles
Brain metastes are substantially reduced, Ai Li is as follows for the structural formula of Buddhist nun：
Ai Li is prepared at present to replace there are many synthetic methods of Buddhist nun, but mostly finally carry out preparation Ai Li by preparing intermediate
For Buddhist nun, wherein mesosome chemical name is 9- ethyl -6,6- dimethyl -8- hydroxyls -11- oxa-s -6,11- dihydro -5H- benzos [b] click
Azoles -3- formonitrile HCNs, structural formula are as follows：
And it is existing preparation Ai Li for Buddhist nun's intermediate 9- ethyl -6,6- dimethyl -8- hydroxyl -11- oxa-s -6,11- dihydro -
5H- benzos [b] are not suitable for large-scale production, need to carry out multiple radical protection although the method yield of carbazole -3- formonitrile HCNs can manage it
With deprotection reaction, waste is caused, therefore there is an urgent need for a kind of simple, high income preparation wherein mesosome 9- ethyls -6,6- bis-
The method of methyl -8- hydroxyls -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs.
Invention content
A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate；The present invention provides one kind with 2- methoxyl group -5- hydroxyls
- 7,8 dihydronaphthalene -7- ketone of base -8- dimethyl for starting material through chlorination, oxidation reaction, substitution reaction, alkylated reaction,
Ring-closure reaction, substitution reaction, reduction reaction, cyanation obtain 9- ethyl -6,6- dimethyl -8- hydroxyl -11- oxa-s -6,11-
Dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, preparation process is succinct, and raw material is easy to get, and synthesis condition is simple, economic and environment-friendly, production
Product yield and product purity are high, are advantageously implemented industrialization, reduce manufacturing cost, suitable for producing in enormous quantities, seek newly
Anticancer drug Ai Li is meaningful for the economic technology of Buddhist nun for Ai Li for the preparation method of Buddhist nun's intermediate.
To achieve the above object, the specific route of preparation method of the invention is as follows：
Technical scheme of the present invention is implemented as follows：
A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate, comprises the following steps that：
A. chlorination
1. -7,8 dihydronaphthalene -7- ketone of 2- methoxyl group -5- hydroxyl -8- dimethyl is added to the body of organic solvent and water first
Product is than being 1:1.1~1:In 1.5 mixed liquor, chlorinating agent is secondly added in, reaction is stirred well to and terminates, be adjusted to sodium hydroxide
PH value is 9~10, finally filters, is dry, obtaining chloro- 8- dimethyl -7,8 dihydronaphthalene of 2- methoxyl group -5- hydroxyls 7- 2..
B. oxidation reaction
Acid solution is prepared by acid is soluble in water first, is added in oxidant, is secondly added in organic solvent and the volume ratio of water is
1:1.2~1:1.6 mixed liquor, stirs evenly, heating water bath to 100 DEG C, be eventually adding the 2- methoxyl groups that are obtained in step A-
2. chloro- 8- dimethyl -7,8 dihydronaphthalene of 5- hydroxyls 7-, is stirred continuously, reaction a period of time is cooled down, filtered, dried, obtain to terminating
To chloro- -5,6,7,8 naphthane -5- ketone of 8- dimethyl of 2- methoxyl groups -7- 3..
C. substitution reaction
Chloro- -5,6,7,8 naphthane -5- ketone of 8- dimethyl of 2- methoxyl groups -7- that Sodamide and step B are obtained is 3. by object
The ratio between amount of matter is 1:1~1:It is added in reaction vessel after 1.3 mixing, then adds in 40~80ml of liquefied ammonia, it is stirred at room temperature 1~
3 hours, TLC detections terminated, and reaction solution is poured into ice water and is filtered, 2- methoxyl group -7- amino -8- two is obtained by filtration cakes torrefaction
- 5,6,7,8 naphthane -5- ketone of methyl is 4..
D. alkylated reaction
Aqueous slkali is prepared by alkali is soluble in water, and the volume ratio for adding in organic solvent and water is 1:1.5~1:2.5 mixing
Liquid adds in the 2- methoxyl group -7- amino -8- dimethyl that alkylating reagent is obtained with step C after stirring
4. -5,6,7,8 naphthane -5- ketone are 1 by the ratio between amount of substance:1.4~1：1.7 mixture is protected in nitrogen
Under be sufficiently mixed stirring, occur alkylated reaction at 80~90 DEG C, generate N-2- methoxyl groups -7- [(3- nitrobenzophenones) ammonia
Base] -8- dimethyl -5,6,7,8 naphthane -5- ketone 5..
E. ring-closure reaction
By -5,6,7,8 tetrahydrochysene of the N-2- methoxyl groups -7- generated in step D [(3- nitrobenzophenones) amino] -8- dimethyl
Naphthalene -5- ketone 5. add in fill organic solvent and water volume ratio be 1:1.5~1:In the reaction vessel of 2 mixed liquor, ring is added in
Mixture is sufficiently stirred, and 3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa- -6 are generated through ultraviolet light-initiated ring-closure reaction,
11- dihydro -5H- benzos [b] carbazole is 6..
F. substitution reaction
3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa- -6, the 11- dihydro -5H- benzos that will be generated in step E
6. [b] carbazole is 1 by the ratio between amount of substance with chloroethanes:0.5~1:0.8 mixing, is dissolved in tetrahydrofuran, adds in catalyst,
It is sufficiently mixed stirring under nitrogen protection, generates 9- ethyl -3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa-s -6,11-
Dihydro -5H- benzos [b] carbazole is 7..
G. reduction reaction
It is first 1 by volume by hydroiodic acid and ethyl alcohol:1~1:1.5, in being mixed in container, secondly add in step F
9- ethyls -3- nitro -6,6- dimethyl -8- methoxyl groups -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole of middle generation 7.,
It is stirred continuously, reacts at room temperature 2~4 hours, generation reduction reaction, generation 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyls -
11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole is 8..
H. cyanation
First by 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyl -11- oxa-s -6, the 11- dihydro generated in step G -
5H- benzos [b] carbazole 8. add in fill organic solvent and hydrochloric acid volume ratio be 1:1.2~1:The reaction of 1.5 mixed liquor is held
In device, metallic catalyst is added under water-less environment, is sufficiently mixed stirring, after reacting 12~15 hours, TLC detections are completed,
It is secondary that it is cuprous that sodium nitrite and nitrile are added in into reaction vessel by the ratio between amount of substance is 1:1~1:1.2 mixture, the reaction was continued
8~10 hours, cyanation occurs, generates 9- ethyl -6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzos
9., i.e. Ai Li replaces Buddhist nun's intermediate to [b] carbazole -3- formonitrile HCNs.
Organic solvent in the A is that the ratio between trifluoromethanesulfanhydride anhydride and phosphorus oxychloride volume are 1:1 mixed liquor, the chlorine
Agent is chloric acid acid anhydride.
Acid in the step B is 90% sulfuric acid, and the oxidant is sodium dichromate or potassium bichromate, described organic molten
Agent is acetonitrile, n,N-Dimethylformamide (DMF), toluene, Isosorbide-5-Nitrae dioxane or tetrahydrofuran, the reaction time for 10~
12 hours.
Alkali in the step D is sodium hydroxide, potassium hydroxide or lithium hydroxide, and the organic solvent is triethylamine, pyrrole
Pyridine, N- methylmorpholines or diisopropylethylamine, the alkylating reagent are 3- bromo nitrobenzenes.
Solvent in the step E is N-Methyl pyrrolidone or tert-pentyl alcohol, and the cyclizing agent is benzoyl peroxide.
Catalyst in the step F is alchlor.
Organic solvent in the step H is ethyl alcohol, ether, benzene or oil, and the metallic catalyst is iron or tin.
Illustrate the present invention in detail below：
A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate, comprises the following steps that：
A. chlorination
1. -7,8 dihydronaphthalene -7- ketone of 2- methoxyl group -5- hydroxyl -8- dimethyl is added to the body of organic solvent and water first
Product is than being 1:1.1~1:In 1.5 mixed liquor, chlorinating agent is secondly added in, reaction is stirred well to and terminates, be adjusted to sodium hydroxide
PH value is 9~10, finally filters, is dry, obtaining chloro- 8- dimethyl -7,8 dihydronaphthalene of 2- methoxyl group -5- hydroxyls 7- 2..
The purpose of the organic solvent used in step A is to dissolve starting material 2- methoxyl group -5- hydroxyl -8- diformazans
- 7,8 dihydronaphthalene -7- ketone of base is 1..
It is 9~10 to adjust pH value, is to ensure that reaction process intermediate ion is precipitated, yield is higher.
B. oxidation reaction
Acid solution is prepared by acid is soluble in water first, is added in oxidant, is secondly added in organic solvent and the volume ratio of water is
1:1.2~1:1.6 mixed liquor, stirs evenly, heating water bath to 100 DEG C, be eventually adding the 2- methoxyl groups that are obtained in step A-
2. chloro- 8- dimethyl -7,8 dihydronaphthalene of 5- hydroxyls 7-, is stirred continuously, reaction a period of time is cooled down, filtered, dried, obtain to terminating
To chloro- -5,6,7,8 naphthane -5- ketone of 8- dimethyl of 2- methoxyl groups -7- 3..
Heating water bath is to reduce reaction impurities, ensures that reaction yield is higher to 100 DEG C in step B.
C. substitution reaction
Chloro- -5,6,7,8 naphthane -5- ketone of 8- dimethyl of 2- methoxyl groups -7- that Sodamide and step B are obtained is 3. by object
The ratio between amount of matter is 1:1~1:It is added in reaction vessel after 1.3 mixing, then adds in 40~80ml of liquefied ammonia, it is stirred at room temperature 1~
3 hours, TLC detections terminated, and reaction solution is poured into ice water and is filtered, 2- methoxyl group -7- amino -8- two is obtained by filtration cakes torrefaction
- 5,6,7,8 naphthane -5- ketone of methyl is 4..
D. alkylated reaction
Aqueous slkali is prepared by alkali is soluble in water, and the volume ratio for adding in organic solvent and water is 1:1.5~1:2.5 mixing
Liquid adds in 2- methoxyl group -7- amino -8- dimethyl -5,6 that alkylating reagent is obtained with step C, 7,8 naphthane -5- after stirring
4. ketone is 1 by the ratio between amount of substance:1.4~1：1.7 mixture is sufficiently mixed stirring under nitrogen protection, in 80~90 DEG C
Lower generation alkylated reaction, generation N-2- methoxyl groups -7- [(3- nitrobenzophenones) amino] -8- dimethyl -5,6,7,8 naphthanes -
5- ketone is 5..
The alkylating reagent added in step D is to make -5,6,7,8 tetrahydrochysene of 2- methoxyl group -7- amino -8- dimethyl
4. naphthalene -5- ketone is alkylated, easily generate alkylate.
E. ring-closure reaction
By -5,6,7,8 tetrahydrochysene of the N-2- methoxyl groups -7- generated in step E [(3- nitrobenzophenones) amino] -8- dimethyl
Naphthalene -5- ketone 5. add in fill organic solvent and water volume ratio be 1:1.5~1:In the reaction vessel of 2 mixed liquor, ring is added in
Mixture is sufficiently stirred, and 3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa- -6 are generated through ultraviolet light-initiated ring-closure reaction,
11- dihydro -5H- benzos [b] carbazole is 6..
In step D add in cyclizing agent be in order to promote N-2- methoxyl groups -7- [(3- nitrobenzophenones) amino] -8- dimethyl -
5,6,7,8 naphthane -5- ketone 5. under ultraviolet light cyclization Cheng Xin product, convenient for reaction.
F. substitution reaction
3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa- -6, the 11- dihydro -5H- benzos that will be generated in step E
6. [b] carbazole is 1 by the ratio between amount of substance with chloroethanes:0.5~1:0.8 mixing, is dissolved in tetrahydrofuran, adds in catalyst,
It is sufficiently mixed stirring under nitrogen protection, generates 9- ethyl -3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa-s -6,11-
Dihydro -5H- benzos [b] carbazole is 7..
G. reduction reaction
It is first 1 by volume by hydroiodic acid and ethyl alcohol:1~1:1.5, in being mixed in container, secondly add in step F
9- ethyls -3- nitro -6,6- dimethyl -8- methoxyl groups -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole of middle generation 7.,
It is stirred continuously, reacts at room temperature 2~4 hours, generation reduction reaction, generation 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyls -
11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole is 8..
H. cyanation
First by 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyl -11- oxa-s -6, the 11- dihydro generated in step G -
5H- benzos [b] carbazole 8. add in fill organic solvent and hydrochloric acid volume ratio be 1:1.2~1:The reaction of 1.5 mixed liquor is held
In device, metallic catalyst is added under water-less environment, is sufficiently mixed stirring, after reacting 12~15 hours, TLC detections are completed,
It is secondary that it is cuprous that sodium nitrite and nitrile are added in into reaction vessel by the ratio between amount of substance is 1:1~1:1.2 mixture, the reaction was continued
8~10 hours, cyanation occurs, generates 9- ethyl -6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzos
9., i.e. Ai Li replaces Buddhist nun's intermediate to [b] carbazole -3- formonitrile HCNs.
Compared with prior art, the present invention it has the advantages that：
A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate；The present invention provides one kind with 2- methoxyl group -5- hydroxyls
- 7,8 dihydronaphthalene -7- ketone of base -8- dimethyl for starting material through chlorination, oxidation reaction, substitution reaction, alkylated reaction,
Ring-closure reaction, substitution reaction, reduction reaction, cyanation obtain 9- ethyl -6,6- dimethyl -8- hydroxyl -11- oxa-s -6,11-
Dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, preparation process is succinct, and raw material is easy to get, and synthesis condition is simple, economic and environment-friendly, production
Product yield and product purity are high, are advantageously implemented industrialization, reduce manufacturing cost, suitable for producing in enormous quantities, seek newly
Anticancer drug Ai Li is meaningful for the economic technology of Buddhist nun for Ai Li for the preparation method of Buddhist nun's intermediate.
Specific embodiment
Present invention is further elaborated in following combination specific embodiment.
Embodiment 1
A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate, comprises the following steps that：
A. chlorination
In 500ml reaction vessels, by 2- methoxyl group -5- hydroxyl -8- dimethyl -7,8 dihydronaphthalene -7- ketone 1. (11g,
It 0.25mol) is added in the mixed liquor of trifluoromethanesulfanhydride anhydride 40ml, phosphorus oxychloride 40ml, water 90ml, adds in chlorinating agent chloric acid
Acid anhydride is stirred well to reaction and terminates, and it is 9 to be adjusted to pH value with sodium hydroxide, finally filters, is dry, obtaining 2- methoxyl group -5- hydroxyls
Chloro- 8- dimethyl -7,8 dihydronaphthalene of 7- is 2. (9.02g, 0.82mol).
B. oxidation reaction
90% sulfuric acid 35ml is dissolved in water 65ml first, oxidant sodium dichromate is added in, secondly adds in N, N- dimethyl
The mixed liquor of formamide (DMF) 35ml and water 40ml, stirs evenly, heating water bath is eventually adding in step A and obtains to 100 DEG C
Chloro- 8- dimethyl -7,8 dihydronaphthalene of 2- methoxyl group -5- hydroxyls 7- 2. (9.02g, 0.82mol), be stirred continuously, react 10 hours
To terminating, cool down, filter, dry, obtain the chloro- 8- dimethyl -5,6 of 2- methoxyl groups -7-, 7,8 naphthane -5- ketone 3. (8.39g,
1.28mol)。
C. substitution reaction
The chloro- 8- dimethyl -5,6 of 2- methoxyl groups -7- that Sodamide (3.82g, 0.67mol) and step B are obtained, 7,8 four
3. hydrogen naphthalene -5- ketone is added to after (8.39g, 1.28mol) is mixed in reaction vessel, then add in liquefied ammonia 55ml, be stirred at room temperature 1.5
Hour, TLC detections terminate, and reaction solution is poured into ice water and is filtered, 2- methoxyl group -7- amino -8- two is obtained by filtration cakes torrefaction
Methyl -5,6,7,8 naphthane -5- ketone are 4. (6.88g, 2.61mol).
D. alkylated reaction
Sodium hydroxide (10g, 0.28mol) is dissolved in water 40ml, the mixed liquor of triethylamine 20ml and water 40ml is added in, stirs
2- methoxyl group -7- amino -8- the diformazans that alkylating reagent 3- bromo nitrobenzenes (2.94g, 1.6mol) are obtained with step C are added in after mixing
Base -5,6, the mixture of 7,8 naphthane -5- ketone 4. (6.88g, 2.61mol), is sufficiently mixed stirring, in 82 under nitrogen protection
Alkylated reaction occurs at DEG C, generates N-2- methoxyl groups -7- [(3- nitrobenzophenones) amino] -8- dimethyl -5,6,7,8 tetrahydrochysenes
Naphthalene -5- ketone is 5. (8.01g, 3.38mol).
E. ring-closure reaction
By -5,6,7,8 tetrahydrochysene of the N-2- methoxyl groups -7- generated in step D [(3- nitrobenzophenones) amino] -8- dimethyl
5. (8.01g, 3.38mol) addition fills N-Methyl pyrrolidone 65ml, the mixed liquor with water 100ml to naphthalene -5- ketone, adds in cyclization
Agent benzoyl peroxide, is sufficiently stirred, through ultraviolet light-initiated ring-closure reaction generation 3- nitro -6,6- dimethyl -8- methoxyl groups -
11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole is 6. (6.57g, 2.86mol).
F. substitution reaction
3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa- -6, the 11- dihydro -5H- benzos that will be generated in step E
6. (6.57g, 2.86mol) is mixed [b] carbazole with chloroethanes (4.09g, 3.52mol), is dissolved in 110ml in tetrahydrofuran, is added in
Catalyst alchlor is sufficiently mixed stirring under nitrogen protection, generates 9- ethyl -3- nitro -6,6- dimethyl -8- methoxies
Base -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole is 7. (8.5g, 2.7mol).
G. reduction reaction
First by hydroiodic acid 80ml and ethyl alcohol 102ml in being mixed in container, the 9- second generated in step F is secondly added in
Base -3- nitro -6,6- dimethyl -8- methoxyl groups -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole 7. (8.5g,
2.7mol), it is stirred continuously, reacts at room temperature 2 hours, reduction reaction occurs, generate 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyls
Base -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole is 8. (6.97g, 4.1mol).
H. cyanation
First by 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyl -11- oxa-s -6, the 11- dihydro generated in step G -
5H- benzos [b] carbazole 8. (6.97g, 4.1mol) addition fill ethyl alcohol 80ml, hydrochloric acid 90ml mixed liquor reaction vessel in,
Metallic catalyst iron is added under water-less environment, is sufficiently mixed stirring, after reacting 12 hours, TLC detections are completed, secondly to reaction
The mixture of sodium nitrite (2.2g, 2.52mol) and nitrile cuprous (4.0g, 1.3mol) is added in container, the reaction was continued 8 hours,
Cyanation, generation 9- ethyl -6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzo [b] carbazoles -3- occurs
Formonitrile HCN is 9. (5.72g, 3.8mol).
Embodiment 2
A kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate, comprises the following steps that：
A. chlorination
In 500ml reaction vessels, by 2- methoxyl group -5- hydroxyl -8- dimethyl -7,8 dihydronaphthalene -7- ketone 1. (26g,
It 0.631mol) is added in the mixed liquor of trifluoromethanesulfanhydride anhydride 80ml, phosphorus oxychloride 80ml, water 88ml, adds in chlorinating agent chloric acid
Acid anhydride is stirred well to reaction and terminates, and it is 9.5 to be adjusted to pH value with sodium hydroxide, finally filters, is dry, obtaining 2- methoxyl group -5- hydroxyls
Chloro- 8- dimethyl -7,8 dihydronaphthalene of base 7- is 2. (20.89g, 1.64mol).
B. oxidation reaction
90% sulfuric acid 60ml is dissolved in water 60ml first, oxidant sodium dichromate is added in, secondly adds in N, N- dimethyl
The mixed liquor of formamide (DMF) 50ml and water 63ml, stirs evenly, heating water bath is eventually adding in step A and obtains to 100 DEG C
Chloro- 8- dimethyl -7,8 dihydronaphthalene of 2- methoxyl group -5- hydroxyls 7- 2. (20.89g, 1.64mol), be stirred continuously, reaction is 11 small
Up to end, cooling, filtering, drying obtain the chloro- 8- dimethyl -5,6 of 2- methoxyl groups -7-, 7,8 naphthane -5- ketone are 3.
(17.01g, 2.26mol).
C. substitution reaction
The chloro- 8- dimethyl -5,6 of 2- methoxyl groups -7- that Sodamide (4.22g, 0.58mol) and step B are obtained, 7,8 four
3. hydrogen naphthalene -5- ketone is added to after (17.01g, 2.26mol) is mixed in reaction vessel, then add in liquefied ammonia 80ml, be stirred at room temperature 3
Hour, TLC detections terminate, and reaction solution is poured into ice water and is filtered, 2- methoxyl group -7- amino -8- two is obtained by filtration cakes torrefaction
Methyl -5,6,7,8 naphthane -5- ketone are 4. (13.6g, 2.34mol).
D. alkylated reaction
Sodium hydroxide (17.8g, 0.5mol) is dissolved in water 50ml, adds in the mixed liquor of triethylamine 40ml and water 52ml,
2- methoxyl group -7- amino-the 8- that alkylating reagent 3- bromo nitrobenzenes (6.45g, 1.63mol) are obtained with step C is added in after stirring
Dimethyl -5,6, the mixture of 7,8 naphthane -5- ketone 4. (13.6g, 2.34mol), is sufficiently mixed stirring under nitrogen protection,
Occur alkylated reaction at 90 DEG C, generate N-2- methoxyl groups -7- [(3- nitrobenzophenones) amino] -8- dimethyl -5,6,7,8 four
Hydrogen naphthalene -5- ketone is 5. (16.44g, 4.59mol).
E. ring-closure reaction
By -5,6,7,8 tetrahydrochysene of the N-2- methoxyl groups -7- generated in step D [(3- nitrobenzophenones) amino] -8- dimethyl
5. (16.44g, 4.59mol) addition fills N-Methyl pyrrolidone 80ml, the mixed liquor with water 120ml to naphthalene -5- ketone, adds in ring
Mixture benzoyl peroxide, is sufficiently stirred, through ultraviolet light-initiated ring-closure reaction generation 3- nitro -6,6- dimethyl -8- methoxyl groups -
11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole is 6. (13.39g, 3.38mol).
F. substitution reaction
3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa- -6, the 11- dihydro -5H- benzos that will be generated in step E
6. (13.39g, 3.38mol) is mixed [b] carbazole with chloroethanes (8.3g, 4.08mol), is dissolved in 130ml in tetrahydrofuran, is added in
Catalyst alchlor is sufficiently mixed stirring under nitrogen protection, generates 9- ethyl -3- nitro -6,6- dimethyl -8- methoxies
Base -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole is 7. (17.78g, 3.6mol).
G. reduction reaction
First by hydroiodic acid 110ml and ethyl alcohol 110ml in being mixed in container, the 9- generated in step F is secondly added in
Ethyl -3- nitro -6,6- dimethyl -8- methoxyl groups -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole 7. (17.78g,
3.6mol), it is stirred continuously, reacts at room temperature 3 hours, reduction reaction occurs, generate 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyls
Base -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole is 8. (14.6g, 7.5mol).
H. cyanation
First by 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyl -11- oxa-s -6, the 11- dihydro generated in step G -
5H- benzos [b] carbazole 8. (14.6g, 7.5mol) addition fill ethyl alcohol 90ml, hydrochloric acid 110ml mixed liquor reaction vessel in,
Metallic catalyst iron is added under water-less environment, is sufficiently mixed stirring, after reacting 13.5 hours, TLC detections are completed, secondly to anti-
The mixture that sodium nitrite (3.3g, 0.85mol) and nitrile cuprous (3.1g, 0.57mol) are added in container is answered, it is 9 small that the reaction was continued
When, cyanation occurs, generates 9- ethyl -6,6- dimethyl -8- hydroxyls -11- oxa-s -6,11- dihydro -5H- benzos [b] click
Azoles -3- formonitrile HCNs are 9. (11.97g, 6.1mol).
It is obvious to a person skilled in the art that the present invention is not limited to the details of above-mentioned exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of from which, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended right
It is required that rather than above description limit, it is intended that all changes that will be fallen within the meaning and scope of the equivalent requirements of the claims
Change is included within the present invention.Any label in claim should not be considered as to the involved claim of limitation.
Based on the embodiments of the present invention, those of ordinary skill in the art are obtained without making creative work
The every other embodiment obtained, shall fall within the protection scope of the present invention.
Claims (7)
1. a kind of anticancer drug Ai Li replaces the preparation method of Buddhist nun's intermediate, the anticancer drug Ai Li replaces Buddhist nun's intermediated chemistry title
For 9- ethyl -6,6- dimethyl -8- hydroxyls -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, structural formula
For：
,
It is characterized in that：The anticancer drug Ai Li is made to comprise the following steps that for the preparation method of Buddhist nun's intermediate：
A. chlorination
1. -7,8 dihydronaphthalene -7- ketone of 2- methoxyl group -5- hydroxyl -8- dimethyl is added to the volume ratio of organic solvent and water first
It is 1:1.1~1:In 1.5 mixed liquor, chlorinating agent is secondly added in, reaction is stirred well to and terminates, pH value is adjusted to sodium hydroxide
It is 9~10, finally filters, is dry, obtaining chloro- 8- dimethyl -7,8 dihydronaphthalene of 2- methoxyl group -5- hydroxyls 7- 2.；
B. oxidation reaction
Acid solution is prepared by acid is soluble in water first, adds in oxidant, the volume ratio for secondly adding in organic solvent and water is 1:1.2
~1:1.6 mixed liquor, stirs evenly, and heating water bath is eventually adding the 2- methoxyl group -5- hydroxyls obtained in step A to 100 DEG C
2. chloro- 8- dimethyl -7,8 dihydronaphthalene of 7-, is stirred continuously, reaction a period of time is cooled down, filtered, dried, obtain 2- first to terminating
Chloro- -5,6,7,8 naphthane -5- ketone of 8- dimethyl of oxygroup -7- is 3.；
C. substitution reaction
Chloro- -5,6,7,8 naphthane -5- ketone of 8- dimethyl of 2- methoxyl groups -7- that Sodamide and step B are obtained is 3. by substance
The ratio between amount is 1:1~1:It is added in reaction vessel after 1.3 mixing, then adds in 40~80ml of liquefied ammonia, it is small to be stirred at room temperature 1~3
When, TLC detections terminate, and reaction solution is poured into ice water and is filtered, 2- methoxyl group -7- amino -8- diformazans are obtained by filtration cakes torrefaction
- 5,6,7,8 naphthane -5- ketone of base is 4.；
D. alkylated reaction
Aqueous slkali is prepared by alkali is soluble in water, and the volume ratio for adding in organic solvent and water is 1:1.5~1:2.5 mixed liquor, is stirred
- 5,6,7,8 naphthane -5- ketone of 2- methoxyl group -7- amino -8- dimethyl that addition alkylating reagent is obtained with step C after mixing is 4.
The ratio between amount by substance is 1:1.4~1：1.7 mixture is sufficiently mixed stirring under nitrogen protection, is issued in 80~90 DEG C
Raw alkylated reaction, generates N-2- methoxyl groups -7- [(3- nitrobenzophenones) amino] -8- dimethyl -5,6,7,8 naphthane -5- ketone
⑤；
E. ring-closure reaction
By -5,6,7,8 naphthane -5- of the N-2- methoxyl groups -7- generated in step D [(3- nitrobenzophenones) amino] -8- dimethyl
Ketone 5. add in fill organic solvent and water volume ratio be 1:1.5~1:In the reaction vessel of 2 mixed liquor, cyclizing agent is added in,
It is sufficiently stirred, through ultraviolet light-initiated ring-closure reaction generation 3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa-s -6,11- bis-
Hydrogen -5H- benzos [b] carbazole is 6.；
F. substitution reaction
3- nitro -6,6- dimethyl -8- methoxyl groups -11- oxa-s -6,11- dihydro -5H- benzos [b] click that will be generated in step E
6. azoles is 1 by the ratio between amount of substance with chloroethanes:0.5~1:0.8 mixing, is dissolved in tetrahydrofuran, catalyst is added in, in nitrogen
It is sufficiently mixed stirring under protection, generation 9- ethyl -3- nitro -6,6- dimethyl -8- methoxyl group -11- oxa-s -6,11- dihydro -
5H- benzos [b] carbazole is 7.；
G. reduction reaction
It is first 1 by volume by hydroiodic acid and ethyl alcohol:1~1:1.5 in container in being mixed, and secondly adds in raw in step F
Into 9- ethyls -3- nitro -6,6- dimethyl -8- methoxyl groups -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole 7., constantly
Stirring reacts at room temperature 2~4 hours, and reduction reaction occurs, and generates 9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyl -11- oxygen
Miscellaneous -6,11- dihydro -5H- benzos [b] carbazole is 8.；
H. cyanation
9- ethyl -3- nitro -6,6- dimethyl -8- hydroxyl -11- oxa- -6, the 11- dihydros -5H- that will be generated in step G first
Benzo [b] carbazole 8. add in fill organic solvent and hydrochloric acid volume ratio be 1:1.2~1:The reaction vessel of 1.5 mixed liquor
It is interior, metallic catalyst is added under water-less environment, is sufficiently mixed stirring, after reacting 12~15 hours, TLC detections are completed, secondly
It by the ratio between amount of substance is 1 that it is cuprous that sodium nitrite and nitrile are added in into reaction vessel:1~1:1.2 mixture, the reaction was continued 8
~10 hours, cyanation, generation occurs
9- ethyl -6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs 9., i.e. Ai Li
For Buddhist nun's intermediate.
2. anticancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that：In the A
Organic solvent be the ratio between trifluoromethanesulfanhydride anhydride and phosphorus oxychloride volume be 1:1 mixed liquor, the chlorinating agent are chloric acid acid anhydride.
3. anticancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that：The step
The sulfuric acid that acid in B is 90%, the oxidant are sodium dichromate or potassium bichromate, and the organic solvent is acetonitrile, N, N- diformazans
Base formamide（DMF）, toluene, Isosorbide-5-Nitrae dioxane or tetrahydrofuran, the reaction time is 10~12 hours.
4. anticancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that：The step
Alkali in D is sodium hydroxide, potassium hydroxide or lithium hydroxide, the organic solvent is triethylamine, pyridine, N- methylmorpholines or
Diisopropylethylamine, the alkylating reagent are 3- bromo nitrobenzenes.
5. anticancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that：The step
Solvent in E is N-Methyl pyrrolidone or tert-pentyl alcohol, and the cyclizing agent is benzoyl peroxide.
6. anticancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that：The step
Catalyst in F is alchlor.
7. anticancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that：The step
Organic solvent in H is ethyl alcohol, ether, benzene or oil, and the metallic catalyst is iron or tin.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020193181A (en) * | 2019-05-30 | 2020-12-03 | 東ソー株式会社 | Method for producing aromatic nitrile compound |
| US11014919B2 (en) | 2018-12-07 | 2021-05-25 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of alectinib |
| US11098037B2 (en) | 2017-07-05 | 2021-08-24 | Fresenius Kabi Oncology Ltd. | Process for preparing alectinib or a pharmaceutically acceptable salt thereof |
-
2018
- 2018-01-19 CN CN201810051599.XA patent/CN108264476A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11098037B2 (en) | 2017-07-05 | 2021-08-24 | Fresenius Kabi Oncology Ltd. | Process for preparing alectinib or a pharmaceutically acceptable salt thereof |
| US11465999B2 (en) | 2017-07-05 | 2022-10-11 | Fresenius Kabi Oncology Ltd. | Process for preparing Alectinib or a pharmaceutically acceptable salt thereof |
| US11014919B2 (en) | 2018-12-07 | 2021-05-25 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of alectinib |
| JP2020193181A (en) * | 2019-05-30 | 2020-12-03 | 東ソー株式会社 | Method for producing aromatic nitrile compound |
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