CN114591226B - 一种烟醛衍生物的制备方法 - Google Patents
一种烟醛衍生物的制备方法 Download PDFInfo
- Publication number
- CN114591226B CN114591226B CN202210267986.3A CN202210267986A CN114591226B CN 114591226 B CN114591226 B CN 114591226B CN 202210267986 A CN202210267986 A CN 202210267986A CN 114591226 B CN114591226 B CN 114591226B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- nicotinaldehyde
- formula
- mmol
- 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
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical class O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 9
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- 238000006751 Mitsunobu reaction Methods 0.000 claims abstract description 5
- 238000006959 Williamson synthesis reaction Methods 0.000 claims abstract description 5
- -1 benzyl halide Chemical class 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 6
- 239000003377 acid catalyst Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000000958 aryl methylene group Chemical group 0.000 claims description 6
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229920002866 paraformaldehyde Polymers 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 5
- 229940100198 alkylating agent Drugs 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 claims description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 4
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 3
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract 1
- 238000005805 hydroxylation reaction Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 125000005605 benzo group Chemical group 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000007858 starting material Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VGLYWIHEKHLBAO-UHFFFAOYSA-N 6-chloro-2-methoxy-5-(trifluoromethyl)pyridine-3-carbaldehyde Chemical compound ClC1=NC(=C(C=O)C=C1C(F)(F)F)OC VGLYWIHEKHLBAO-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RNXQQZNOSYBFTN-SECBINFHSA-N (1r)-4-bromo-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC=C(Br)C2=C1[C@H](O)CC2 RNXQQZNOSYBFTN-SECBINFHSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- RZZIQSBRKKMUKG-UHFFFAOYSA-N 2-chloro-6-methoxy-3-(trifluoromethyl)pyridine Chemical compound COC1=CC=C(C(F)(F)F)C(Cl)=N1 RZZIQSBRKKMUKG-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- HNININUZIFIRHF-UHFFFAOYSA-N 5,6-dichloro-2-methoxypyridine-3-carbaldehyde Chemical compound ClC=1C(=NC(=C(C=O)C=1)OC)Cl HNININUZIFIRHF-UHFFFAOYSA-N 0.000 description 2
- BUJFLTNYWUEROF-UHFFFAOYSA-N 5-(bromomethyl)-2,1,3-benzoxadiazole Chemical compound C1=C(CBr)C=CC2=NON=C21 BUJFLTNYWUEROF-UHFFFAOYSA-N 0.000 description 2
- ZBUDXVRNLXVOMU-AWEZNQCLSA-N 6-[[(1S)-4-bromo-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxy-5-(trifluoromethyl)pyridine-3-carbaldehyde Chemical compound COC1=C(C=O)C=C(C(F)(F)F)C(O[C@@H]2C3=CC=CC(Br)=C3CC2)=N1 ZBUDXVRNLXVOMU-AWEZNQCLSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- KSHOVMIYYKZDGI-AWEZNQCLSA-N COC1=NC(=C(C=C1C=O)Cl)O[C@H]2CCC3=C2C=CC=C3Br Chemical compound COC1=NC(=C(C=C1C=O)Cl)O[C@H]2CCC3=C2C=CC=C3Br KSHOVMIYYKZDGI-AWEZNQCLSA-N 0.000 description 2
- JUPKLFYCXSNEPA-UHFFFAOYSA-N COC1=NC(=C(C=C1CO)Cl)Cl Chemical compound COC1=NC(=C(C=C1CO)Cl)Cl JUPKLFYCXSNEPA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- CRYZJWACYQGRDW-UHFFFAOYSA-N 1-(bromomethyl)-2-chloro-3-iodobenzene Chemical compound ClC1=C(I)C=CC=C1CBr CRYZJWACYQGRDW-UHFFFAOYSA-N 0.000 description 1
- IXGDCKOOLQXQRS-UHFFFAOYSA-N 1-(bromomethyl)-2-fluoro-3-iodobenzene Chemical compound BrCC1=C(C(=CC=C1)I)F IXGDCKOOLQXQRS-UHFFFAOYSA-N 0.000 description 1
- PCVPVMZNHMYIDP-UHFFFAOYSA-N 2,3-dichloro-6-methoxypyridine Chemical compound COC1=CC=C(Cl)C(Cl)=N1 PCVPVMZNHMYIDP-UHFFFAOYSA-N 0.000 description 1
- UPWAAFFFSGQECJ-UHFFFAOYSA-N 2,6-dichloro-3-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Cl)N=C1Cl UPWAAFFFSGQECJ-UHFFFAOYSA-N 0.000 description 1
- KDGFTIJXTPBJBP-UHFFFAOYSA-N 2-bromo-1-(bromomethyl)-3-iodobenzene Chemical compound BrCC1=CC=CC(I)=C1Br KDGFTIJXTPBJBP-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种式I所示烟醛衍生物的制备方法，具体通过羟甲基化反应、烷基化反应、氧化反应、羟基化反应、Mitsunobu反应或Williamson反应等步骤，制备得到本发明的烟醛衍生物。该方法既避免了现有路线中三氟甲基化收率过低的问题，也更有利于实现通式中基团的灵活替换，该制备方法的通用性更好，更适合药物合成中此类烟醛衍生物的大规模制备。
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种烟醛衍生物的制备方法。
背景技术
烟醛衍生物属于吡啶类化合物，其在药物化学中起着重要作用，往往与药物活性直接相关，常被作为药物合成的关键中间体。目前关于式I结构烟醛衍生物的制备主要有两种方法：
其中，G选自氯或三氟甲基；
X选自卤素；
R1选自C1～C5烷基或芳基亚甲基；
A选自O或N；
R2选自C1～C5烷基、卤代芳基亚甲基或卤代取代苄基。
专利CN112399874A公开了含烟醛衍生物的合成实施例，具体路线如下：
此路线并未提供三氟甲基化反应的收率，且本发明人重现该条件时收率较低并不利于大规模制备产品；其次作为药物化学分子的关键中间体，该路线并不利于甲氧基的衍生化替换。
专利CN110799509A公开了一种合成烟醛衍生物的方法，具体路线如下：
此路线步骤少，收率为63％，对于单一化合物适用，若甲氧基被其它敏感基团替代，那么上述路线就不适用，原因在于此位置很容易在强碱条件下分解。例如，发明人采用该方法合成如下目标产物：
上述第二步的反应原料就是将甲氧基替换成苯并二噁唑苄氧基，但是在此反应中完全没有产物生成，得到的是脱苯并二噁唑苄基的产物，结构如下所示。核磁数据：1H NMR(400MHz,DMSO)δ12.55(s,1H),8.08(d,J＝8.6Hz,1H),6.79(d,J＝8.5Hz,1H)。由此说明CN110799509A公开的方法并不适用于取代苄氧基代替甲氧基后的反应。
因此如何找到一种新的合成策略，一方面解决上述专利路线中三氟甲基化收率低的缺点，另一方面实现后期上述通式中基团的有效替换，是制备此类烟醛衍生物的关键。
发明内容
为了克服上述现有技术的不足，本发明的目的在于提供一种烟醛衍生物的制备方法。
本发明解决上述技术问题的技术方案如下：
本发明提供了一种烟醛衍生物的制备方法，其特征在于，包括如下步骤：
(1)在酸催化剂存在下，式II化合物与多聚甲醛/甲醛经羟甲基化反应得式III化合物；
(2)式III化合物先经烷基化反应再经氧化反应，或先经氧化反应再经烷基化反应得式VI化合物；
其中，所述烷基化反应使用烷基化试剂和碱性试剂；所述氧化反应使用氧化试剂；
(3)式VI化合物与碱性试剂反应得式VII化合物；
(4)式VII化合物经Mitsunobu反应，或经Williamson反应得式I化合物，即目标产物；
具体路线如下：
其中，G选自氯或三氟甲基；
X选自卤素；
R1选自C1～C5烷基或芳基亚甲基；
A选自O或N；
R2选自C1～C5烷基、卤代芳基亚甲基或卤代取代苄基；
进一步的，所述步骤(1)中酸催化剂选自浓盐酸、乙酸、乙酰氯/水、氯化锌中的一种或几种；
进一步的，所述步骤(1)中式II化合物与多聚甲醛/甲醛、酸催化剂的摩尔比为1:1～3:1～10；
进一步的，所述步骤(1)的反应温度为120～150℃，反应时间为10～20h；
进一步的，所述步骤(2)中烷基化试剂选自碘甲烷、硫酸二甲酯、取代苄卤或取代苄醇；碱性试剂选自碳酸钾、碳酸钠、碳酸铯、碳酸银、氢氧化钠或氢氧化钾；所用原料与烷基化试剂、碱性试剂的摩尔比为1:1～2:1～5；
进一步的，所述步骤(2)中氧化试剂选自PCC氧化剂或PDC氧化剂；所用原料与氧化试剂的摩尔比为1:1～3；
进一步的，所述步骤(2)中烷基化反应的反应温度为0～10℃，氧化反应的反应温度为20～40℃；
进一步的，所述步骤(3)中的碱性试剂选自氢氧化钠、氢氧化钾、四丁基氟化铵或四甲基氟化铵；式VI化合物与碱性试剂的摩尔比为1:1～3；反应温度为20～50℃；
进一步的，所述步骤(4)中Mitsunobu反应所用试剂包括偶氮二甲酸二乙酯/偶氮二甲酸二异丙酯、三苯基膦/三丁基膦、取代苄醇；式VII化合物与取代苄醇、偶氮二甲酸二乙酯/偶氮二甲酸二异丙酯、三苯基膦/三丁基膦的摩尔比为1:1～1.2:1～1.2；
进一步的，所述步骤(4)中Williamson反应所用试剂包括取代苄卤、碱性试剂；所述碱性试剂选自碳酸钾、碳酸钠、碳酸铯、碳酸银、氢氧化钠、氢氧化钾或氢化钠；式VII化合物与取代苄卤、碱性试剂的摩尔比为1:1～1.5:1～3；反应温度为0～40℃。
本发明中化合物的中文命名与结构式有冲突的，以结构式为准；结构式有明显错误的除外。
本发明的有益效果在于：
本发明提供了一种式I结构烟醛衍生物的新合成策略，既避免了现有路线中三氟甲基化收率过低的问题，也更有利于实现通式中基团的灵活替换，该制备方法的通用性更好，更适合药物合成中此类烟醛衍生物的大规模制备。
具体实施方式
以下结合实例说明本发明，但不限制本发明。在本领域内，技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
实施例1：(S)-6-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基-5-(三氟甲基)烟醛的制备
2-氯-6-甲氧基-3-三氟甲基吡啶：在反应瓶中加入原料2，6-二氯-3-三氟甲基吡啶(20g，0.0926mol),甲醇100g，室温下慢慢滴加甲醇钠溶液(6g，0.11mol)，滴完室温搅拌，反应10小时取样LC-MS原料反应完毕后处理反应。后处理：体系过滤，滤液旋干后用二氯甲烷和水萃取，有机相用无水硫酸钠干燥旋干的白色固体17.6g，收率90％。1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.6Hz,1H),6.73(d,J＝8.5Hz,1H),4.00(s,3H).
6-氯-3-(羟甲基)-5-(三氟甲基)吡啶-2-醇：在耐压瓶中加入2-氯-6-甲氧基-3-三氟甲基吡啶(5g，23.5mmol)、多聚甲醛(2.13g，70.5mmol)、乙酰氯12.5ml、乙酸10ml，加入水2.5ml后快速密封150度反应20小时。降温后打开耐压瓶，滴加水，大量固体析出，然后过滤，滤饼用90％的乙腈+10％的水打浆得4.54g，纯度95％，收率85％。1H NMR(400MHz,DMSO)δ7.96(s,1H),4.41(s,2H).
(6-氯-2-甲氧基-5-(三氟甲基)吡啶-3-基)甲醇：在反应瓶中加入6-氯-3-(羟甲基)-5-(三氟甲基)吡啶-2-醇(1g，4.4mmol)、DMF5ml、碳酸钾(912mg，6.6mmol)，40℃下滴加硫酸二甲酯(665mg，5.27mmol)，反应2小时完毕。后处理：体系加EA和水萃取，有机相用无水硫酸钠干燥脱溶，得744mg，收率70％。1H NMR(400MHz,DMSO)δ8.06(s,1H),5.54(s,1H),4.48(d,J＝4.0Hz,2H),3.97(s,3H).
6-氯-2-甲氧基-5-(三氟甲基)烟醛：在反应瓶中加入PCC(892mg，4.14mmol)、DCM10ml，加入分子筛500mg，室温下滴加(6-氯-2-甲氧基-5-(三氟甲基)吡啶-3-基)甲醇(500mg，2.07mmol)的DCM溶液，滴加完毕反应2小时。后处理：体系加活性炭除色，然后用硅藻土过滤，滤液脱溶后得486mg白色黏稠晶体，收率98％。1H NMR(400MHz,CDCl3)δ10.23(s,1H),8.33(s,1H),4.10(s,3H).
6-羟基-2-甲氧基-5-(三氟甲基)烟醛：在反应瓶中加入6-氯-2-甲氧基-5-(三氟甲基)烟醛(500mg，2.09mmol)、四氢呋喃5ml、氢氧化钠(167mg，4.18mmol)，30℃搅拌反应5小时，原料完全转化完。用饱和氯化铵溶液调体系pH至6～7，然后用二甲基四氢呋喃萃取体系，有机相干燥脱溶得439mg白色固体，纯度96％，收率95％。
(S)-6-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基-5-(三氟甲基)烟醛：在反应瓶中加入(R)-4-溴-2,3-二氢-1H-茚-1-醇(385.4mg，1.81mmol)、6-羟基-2-甲氧基-5-(三氟甲基)烟醛(400mg，1.81mmol)、乙酸乙酯5ml、三苯基膦(570mg，2.17mmol)冰浴搅拌，氮气保护，缓慢滴加偶氮二甲酸二乙酯(342μL，2.17mmol)，滴加完毕后冰浴反应2小时。后处理：体系加乙酸乙酯和水萃取，有机相脱溶后过柱(PE:EA＝25:1)得640mg白色固体，收率85％。1H NMR(400MHz,CDCl3)δ10.23(s,1H),8.36(s,1H),7.50(d,J＝7.9Hz,1H),7.37(d,J＝7.5Hz,1H),7.14(t,J＝7.7Hz,1H),6.72-6.61(m,1H),4.16(s,3H),3.19(dd,J＝16.5,9.0,4.5Hz,1H),2.96(dd,J＝16.6,6.6Hz,1H),2.82-2.70(m,1H),2.34-2.20(m,1H).
实施例2：6-氯-2-甲氧基-5-(三氟甲基)烟醛的制备
6-氯-2-羟基-5-(三氟甲基)烟醛：在反应瓶中加入PCC(892mg，4.14mmol)、DCM10ml，加入分子筛500mg，室温下滴加6-氯-3-(羟甲基)-5-(三氟甲基)吡啶-2-醇(500mg，2.20mmol)的DCM溶液，滴加完毕反应2小时。后处理：体系用活性炭除色，硅藻土过滤，滤液脱溶后得446mg黄色晶体，收率90％。1H NMR(400MHz,DMSO)δ10.13(s,1H),8.30(s,1H).
6-氯-2-甲氧基-5-(三氟甲基)烟醛：在反应瓶中加入6-氯-2-羟基-5-(三氟甲基)烟醛(1g，4.4mmol)、DMF5ml、碳酸钾(912mg，6.6mmol)，40℃下滴加硫酸二甲酯(665mg，5.27mmol)，反应2小时完毕。后处理：体系加EA和水萃取，有机相用无水硫酸钠干燥脱溶，粗品过柱(PE:EA＝5:1)得685mg，收率65％。1H NMR(400MHz,CDCl3)δ10.23(s,1H),8.33(s,1H),4.10(s,3H).
实施例3：2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-((2-氯-3-碘苯基)氧基)-5-(三氟甲基)烟醛的制备
(2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-氯-5-(三氟甲基)吡啶-3-基)甲醇：在反应瓶中加入6-氯-3-(羟甲基)-5-(三氟甲基)吡啶-2-醇(4.6g，20.21mmol)、DMF15ml，室温下搅拌溶解，加入碳酸钾(4.19g，30.32mmol)，冰浴条件下搅拌，加入5-(溴甲基)苯并[c][1,2,5]恶二唑(4.3g，20.21mmol)，加完后反应2小时停止反应。体系在冰浴条件下滴加水，待析出大量固体后过滤，滤饼烘干得6.54g，收率90％。1H NMR(400MHz,DMSO)δ8.11(s,1H),8.10–8.06(m,2H),7.70(d,J＝10.0Hz,1H),5.60(t,J＝5.5Hz,1H),5.56(s,2H),4.60(d,J＝5.4Hz,2H).
2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-氯-5-(三氟甲基)烟醛：在反应瓶中加入PCC(6.16g，28.58mmol)、DCM20ml，加入分子筛500mg，室温下滴加(2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-氯-5-(三氟甲基)吡啶-3-基)甲醇(5.14g，14.29mmol)的DCM溶液,滴加完毕反应2小时。后处理：体系用活性炭除色，硅藻土过滤，滤液脱溶后得5g白色固体，收率98％。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.52(s,1H),8.27(s,1H),8.13(dd,J＝9.3,0.8Hz,1H),7.78(dd,J＝9.3,1.3Hz,1H),5.73(d,J＝1.1Hz,2H).
2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-羟基-5-(三氟甲基)烟醛：在反应瓶中加入原料2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-氯-5-(三氟甲基)烟醛(3g，8.39mmol)，加入四氢呋喃40ml，搅拌溶解，室温下加入四甲基氟化铵(3.125g，33.56mmol)，反应3小时结束，体系加水析出固体，过滤，滤饼烘干得2.76g，收率97％。1H NMR(400MHz,DMSO)δ10.14(s,1H),8.23(d,J＝4.7Hz,2H),8.14–8.09(m,1H),7.73(dd,J＝9.3,1.2Hz,1H),5.65(s,2H).
2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-((2-氯-3-碘苯基)氧基)-5-(三氟甲基)烟醛：在反应瓶中加入原料2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-羟基-5-(三氟甲基)烟醛(556mg，1.639mmol)，DMF2ml，冰浴下加入碳酸钾(340mg，2.46mmol)，搅拌，滴加原料1-(溴甲基)-2-氯-3-碘苯(679mg，2.05mmol)的DMF溶液，滴完反应2小时结束。体系加水析出固体过滤，滤饼烘干得926.6mg,收率96％。1H NMR(400MHz,CDCl3)δ10.30(s,1H),8.37(s,1H),7.95(t,J＝8.9Hz,2H),7.81(d,J＝7.9Hz,1H),7.55(d,J＝9.5Hz,1H),7.39(d,J＝7.6Hz,1H),7.00(t,J＝7.8Hz,1H),5.66(d,J＝10.9Hz,4H).
实施例4：2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-((2-溴-3-碘苯基)氧基)-5-(三氟甲基)烟醛的制备
2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-((2-溴-3-碘苯基)氧基)-5-(三氟甲基)烟醛：在反应瓶中加入原料2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-羟基-5-(三氟甲基)烟醛(556mg，1.639mmol)、DMF2ml，冰浴下加入碳酸钾(340mg，2.46mmol)，搅拌，滴加原料1-(溴甲基)-2-溴-3-碘苯(770.4mg，2.05mmol)的DMF溶液，滴完反应2小时结束。体系加水析出固体过滤，滤饼烘干得1.03g，收率99％。1H NMR(400MHz,DMSO)δ10.21(s,1H),8.36(s,1H),8.09–8.01(m,2H),7.81(d,J＝7.6Hz,1H),7.63(d,J＝9.4Hz,1H),7.34(d,J＝7.2Hz,1H),7.06(t,J＝7.7Hz,1H),5.72(s,2H),5.59(s,2H).
实施例5：2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-((2-氟-3-碘苯基)氧基)-5-(三氟甲基)烟醛的制备
2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-((2-氟-3-碘苯基)氧基)-5-(三氟甲基)烟醛：在反应瓶中加入原料2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-羟基-5-(三氟甲基)烟醛(500mg，1.474mmol)、DMF2ml，冰浴下加入碳酸钾(305.5mg，2.21mmol)，搅拌，滴加原料1-(溴甲基)-2-氟-3-碘苯(580.24mg，1.842mmol)的DMF溶液，滴完反应2小时结束。体系加水析出固体过滤，滤饼烘干得777mg，收率92％。1H NMR(400MHz,DMSO)δ10.20(s,1H),8.35(s,1H),8.13(s,1H),8.07(d,J＝9.3Hz,1H),7.77(d,J＝6.3Hz,1H),7.69(dd,J＝9.3,1.0Hz,1H),7.40(t,J＝6.7Hz,1H),6.93(t,J＝7.7Hz,1H),5.75(s,2H),5.65(s,2H).
实施例6：(S)-2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-5-氯烟醛的制备
5,6-二氯-3-(羟甲基)吡啶-2-醇：在耐压瓶中加入2,3-二氯-6-甲氧基-吡啶(5g，28.09mmol),多聚甲醛(1.69g，56.18mmol)、乙酰氯12.5ml、乙酸10ml，加入水2.5ml后快速密封150℃反应20小时。降温后打开耐压瓶，滴加水，大量固体析出，然后过滤得4.9g，纯度98％，收率90％。1H NMR(400MHz,DMSO)δ7.76(s,1H),4.34(d,J＝24.9Hz,2H).
(2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-5,6-二氯吡啶-3-基)甲醇：在反应瓶中加入5,6-二氯-3-(羟甲基)吡啶-2-醇(2.7g，13.92mmol)、DMF15ml，室温下搅拌溶解，加入碳酸钾(2.88g，20.88mmol)，冰浴条件下搅拌，加入5-(溴甲基)苯并[c][1,2,5]恶二唑(2.95g，13.92mmol)，加完后反应2小时停止反应。体系在冰浴下滴加水，待大量固体析出后过滤得到4.3g，收率95％。
2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-5,6-二氯烟醛：在反应瓶中加入PCC(3.9g，18.09mmol)、DCM20ml，加入分子筛500mg，室温下滴加(2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-5,6-二氯吡啶-3-基)甲醇(2.95g，9.04mmol)的DCM溶液，滴加完毕反应2小时。后处理：体系用活性炭除色，硅藻土过滤，滤液脱溶后得2.6g白色固体，收率90％。1HNMR(400MHz,CDCl3)δ10.51-10.28(m,1H),8.29-8.12(m,1H),7.95(d,J＝1.0Hz,1H),7.90(d,J＝9.3Hz,1H),7.50(dd,J＝9.3,1.2Hz,1H),5.71-5.48(m,2H).
2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-5-氯-6-羟基烟醛：在反应瓶中加入原料2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-5,6-二氯烟醛(2.6g，8.02mmol)，加入四氢呋喃10ml，搅拌溶解，室温下加入四甲基氟化铵(2.99g，32.08mmol)，反应3小时结束。体系加水析出固体，过滤，滤饼烘干得2.21g，收率90％。
(S)-2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-6-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-5-氯烟醛：在反应瓶中加入原料(R)-4-溴-2,3-二氢-1H-茚-1-醇(132mg，0.619mmol)，2-(苯并[c][1,2,5]恶二唑-5-基甲氧基)-5-氯-6-羟基烟醛(190mg，0.621mmol)、三苯基膦(196mg，0.747mmol)，乙酸乙酯2ml,氮气保护下冰浴搅拌，滴加DEAD(130mg，0.747mmol)。反应过夜。柱层析(石油醚：乙酸乙酯＝8：1)得到272mg白色固体，收率88％。1H NMR(400MHz,CDCl3)δ10.37-10.23(m,1H),8.16(s,1H),7.97-7.83(m,2H),7.48(d,J＝9.1Hz,2H),7.23(d,J＝7.5Hz,1H),7.03(t,J＝7.7Hz,1H),6.55(dd,J＝7.1,5.0Hz,1H),5.60(s,2H),3.17(ddd,J＝16.7,9.0,4.9Hz,1H),3.01-2.88(m,1H),2.71-2.54(m,1H),2.37-2.17(m,1H).
实施例7：(S)-6-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基-5-氯烟醛的制备
(5,6-二氯-2-甲氧基吡啶-3-基)甲醇：在反应瓶中加入5,6-二氯-3-(羟甲基)吡啶-2-醇(1g，5.15mmol)、DMF5ml、碳酸钾(1.07g，7.725mmol)，40℃下滴加硫酸二甲酯(665mg，5.27mmol)，反应2小时完毕。后处理：体系加EA和水萃取，有机相用无水硫酸钠干燥脱溶，得803mg，收率75％。
5,6-二氯-2-甲氧基烟醛：在反应瓶中加入PCC(892mg，4.14mmol)、DCM10ml，加入分子筛500mg，室温下滴加(5,6-二氯-2-甲氧基吡啶-3-基)甲醇(430mg，2.07mmol)的DCM溶液，滴加完毕反应2小时。后处理：体系加活性炭除色，然后用硅藻土过滤，滤液脱溶后得422mg白色固体，收率99％。
6-羟基-2-甲氧基-5-氯烟醛：在反应瓶中加入5,6-二氯-2-甲氧基烟醛(400mg，1.94mmol)、四氢呋喃5ml、氢氧化钠(155.3mg，3.88mmol)，30℃搅拌反应5小时，原料完全转化完。用饱和氯化铵溶液调体系pH至6～7，然后用二甲基四氢呋喃萃取体系，有机相干燥脱溶得345mg白色固体，纯度95％，收率95％。
(S)-6-((4-溴-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基-5-氯烟醛：在反应瓶中加入(R)-4-溴-2,3-二氢-1H-茚-1-醇(340.6mg，1.6mmol)、6-羟基-2-甲氧基-5-氯烟醛(300mg，1.6mmol)、乙酸乙酯5ml、三苯基膦(503.6mg，1.92mmol)，冰浴搅拌，氮气保护，缓慢滴加偶氮二甲酸二乙酯(302μL，1.92mmol)，滴加完毕后冰浴反应2小时。后处理：体系加乙酸乙酯和水萃取，有机相脱溶后过柱(PE:EA＝25:1)得490mg白色固体，收率80％。1H NMR(400MHz,CDCl3)δ10.18(s,1H),8.09(s,1H),7.49(d,J＝7.9Hz,1H),7.40(d,J＝7.5Hz,1H),7.13(t,J＝7.7Hz,1H),6.64(dd,J＝7.1,4.8Hz,1H),4.09(s,3H),3.20(ddd,J＝16.6,9.0,5.0Hz,1H),3.07-2.94(m,1H),2.77-2.68(m,1H),2.37-2.29(m,1H).
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
Claims (5)
1.一种烟醛衍生物的制备方法，其特征在于，包括如下步骤：
(1)在酸催化剂存在下，式II化合物与多聚甲醛或甲醛经羟甲基化反应得式III化合物；所述步骤(1)中酸催化剂选自浓盐酸、乙酸、乙酰氯和水的混合物、氯化锌中的一种或几种；所述步骤(1)中式II化合物与多聚甲醛或甲醛、酸催化剂的摩尔比为1:1～3:1～10；
(2)式III化合物先经烷基化反应再经氧化反应，或先经氧化反应再经烷基化反应得式VI化合物；
其中，所述烷基化反应使用烷基化试剂和碱性试剂；所述氧化反应使用氧化试剂；所述步骤(2)中烷基化试剂选自碘甲烷、硫酸二甲酯、取代苄卤或取代苄醇；碱性试剂选自碳酸钾、碳酸钠、碳酸铯、碳酸银、氢氧化钠或氢氧化钾；所述步骤(2)中氧化试剂选自PCC氧化剂或PDC氧化剂；所用原料与烷基化试剂、碱性试剂的摩尔比为1:1～2:1～5；所用原料与氧化试剂的摩尔比为1:1～3；
(3)式VI化合物与碱性试剂反应得式VII化合物；所述步骤(3)中的碱性试剂选自氢氧化钠、氢氧化钾、四丁基氟化铵或四甲基氟化铵；式VI化合物与碱性试剂的摩尔比为1:1～3；
(4)式VII化合物经Mitsunobu反应，或经Williamson反应得式I化合物，即目标产物；所述步骤(4)中Mitsunobu反应所用试剂为偶氮二甲酸二乙酯或偶氮二甲酸二异丙酯、三苯基膦或三丁基膦、取代苄醇；所述步骤(4)中Williamson反应所用试剂为取代苄卤、碱性试剂；所述碱性试剂选自碳酸钾、碳酸钠、碳酸铯、碳酸银、氢氧化钠、氢氧化钾或氢化钠；式VII化合物与取代苄卤、碱性试剂的摩尔比为1:1～1.5:1～3；
具体路线如下：
其中，G选自氯或三氟甲基；
X选自卤素；
R1选自C1～C5烷基或芳基亚甲基；
A选自O或N；
R2选自C1～C5烷基、卤代芳基亚甲基。
2.根据权利要求1所述的烟醛衍生物的制备方法，其特征在于，所述步骤(1)的反应温度为120～150℃，反应时间为10～20h。
3.根据权利要求1所述的烟醛衍生物的制备方法，其特征在于，所述步骤(2)中烷基化反应的反应温度为0～10℃，氧化反应的反应温度为20～40℃。
4.根据权利要求1所述的烟醛衍生物的制备方法，其特征在于，所述步骤(3)中反应温度为20～50℃。
5.根据权利要求1所述的烟醛衍生物的制备方法，其特征在于，所述步骤(4)中反应温度为0～40℃。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210267986.3A CN114591226B (zh) | 2022-03-17 | 2022-03-17 | 一种烟醛衍生物的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210267986.3A CN114591226B (zh) | 2022-03-17 | 2022-03-17 | 一种烟醛衍生物的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114591226A CN114591226A (zh) | 2022-06-07 |
| CN114591226B true CN114591226B (zh) | 2024-09-17 |
Family
ID=81810795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210267986.3A Active CN114591226B (zh) | 2022-03-17 | 2022-03-17 | 一种烟醛衍生物的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114591226B (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110799509A (zh) * | 2017-04-20 | 2020-02-14 | 吉利德科学公司 | Pd-1/pd-l1抑制剂 |
| CN113637013A (zh) * | 2020-05-11 | 2021-11-12 | 上海长森药业有限公司 | 联芳环链接芳杂环衍生物作为免疫调节剂的制备及其应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210153665A (ko) * | 2019-05-10 | 2021-12-17 | 상하이 하이옌 파마슈티컬 테크놀로지 컴퍼니, 리미티드 | 치환된 페닐프로펜일피리딘 유도체, 이의 제조 방법 및 이의 의약 용도 |
-
2022
- 2022-03-17 CN CN202210267986.3A patent/CN114591226B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110799509A (zh) * | 2017-04-20 | 2020-02-14 | 吉利德科学公司 | Pd-1/pd-l1抑制剂 |
| CN113637013A (zh) * | 2020-05-11 | 2021-11-12 | 上海长森药业有限公司 | 联芳环链接芳杂环衍生物作为免疫调节剂的制备及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114591226A (zh) | 2022-06-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3992666B2 (ja) | カルボン酸誘導体 | |
| JP3202607B2 (ja) | ２−（４−アルコキシ−３−シアノフェニル）チアゾール誘導体の製造法 | |
| CN114292231B (zh) | 一种2-甲基-8-取代基-喹啉及其制备方法 | |
| CN110698467B (zh) | 恩格列净的合成方法 | |
| GB2240104A (en) | Arylvinylamide derivatives | |
| CN114591226B (zh) | 一种烟醛衍生物的制备方法 | |
| JP2004506043A (ja) | シロスタゾールの製造方法 | |
| KR100720220B1 (ko) | 치환 아닐린 화합물의 제조방법 | |
| US10053420B2 (en) | Processes for the preparation of compounds, such as 3-arylbutanals, useful in the synthesis of medetomidine | |
| RU2709493C1 (ru) | Способ получения роксадустата | |
| CN115197261B (zh) | 噁二氮杂硼衍生物的合成方法 | |
| HU208533B (en) | Process for selective etherification of ascorbinic acid derivatives | |
| EP0823907B1 (en) | PROCESS FOR PREPARING (-)-TRANS-N-p-FLUOROBENZOYLMETHYL-4-(p-FLUOROPHENYL)-3-[[3,4-(METHYLENEDIOXY)PHENOXY]METHYL]-PIPERIDINE | |
| CN113735798A (zh) | 一种盐酸罗沙替丁醋酸酯的制备方法 | |
| RU1831473C (ru) | Способ получени производного нафталина | |
| CN106220554B (zh) | 一种芳基吡啶及其衍生物的制备方法 | |
| RU2204552C2 (ru) | Способ получения пропинилового эфира (r)(+)-2-[4-(5-хлор-3-фторпиридин-2-илокси)фенокси]пропионовой кислоты | |
| CN110452165B (zh) | 一种2-甲基吡啶-4-甲酸的制备方法 | |
| JP2585422B2 (ja) | １―（２―ハロエトキシ）―４―（２―アルコキシエチル）ジアルキルベンゼン類及びその合成中間体並びにそれらの製造法 | |
| CN103145613B (zh) | 一种(e)-3-(2-环丙基-4-(4-氟苯基))喹啉-2-丙烯醛的合成方法 | |
| CN112321599B (zh) | 一种药物中间体7-氧代-2-氮杂螺[3.5]壬烷的合成方法 | |
| JP3159405B2 (ja) | チエニルエーテル誘導体の製造方法 | |
| KR100277671B1 (ko) | (-)-트랜스-엔-피-플루오르벤조일메틸-4-(피-플루오르페닐)-3-[[3,4-(메틸렌디옥시)페녹시]메틸]-피페리딘 및 약제학적으로 허용되는 부가염의 제조방법 | |
| JP4267107B2 (ja) | ピリジン誘導体およびその製造方法 | |
| CN117964583A (zh) | 一种恩格列净手性中间体的制备方法 |
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 |