WO2022174540A1 - 一种扎来普隆的制备方法 - Google Patents
一种扎来普隆的制备方法 Download PDFInfo
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- WO2022174540A1 WO2022174540A1 PCT/CN2021/102459 CN2021102459W WO2022174540A1 WO 2022174540 A1 WO2022174540 A1 WO 2022174540A1 CN 2021102459 W CN2021102459 W CN 2021102459W WO 2022174540 A1 WO2022174540 A1 WO 2022174540A1
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- Prior art keywords
- zaleplon
- preparation
- nitrobenzaldehyde
- present
- compound
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- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960004010 zaleplon Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 11
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000005580 one pot reaction Methods 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical group CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 229940107816 ammonium iodide Drugs 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- BFKYQYMHJANOTR-UHFFFAOYSA-N 2h-pyrimidine-1-carbonitrile Chemical compound N#CN1CN=CC=C1 BFKYQYMHJANOTR-UHFFFAOYSA-N 0.000 claims description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-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
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical group CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-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
- 238000006699 reductive acetylation reaction Methods 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- PAOHAQSLJSMLAT-UHFFFAOYSA-N 1-butylperoxybutane Chemical compound CCCCOOCCCC PAOHAQSLJSMLAT-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 abstract description 3
- 150000003624 transition metals Chemical class 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000010523 cascade reaction Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 4
- 206010022437 insomnia Diseases 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000004799 sedative–hypnotic effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- MTSPUUDCFHSNRX-UHFFFAOYSA-N 3-bromo-3-(3-nitrophenyl)prop-2-enal Chemical compound [O-][N+](=O)C1=CC=CC(C(Br)=CC=O)=C1 MTSPUUDCFHSNRX-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003326 hypnotic agent Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- AFZTYHRVDOKRKV-UHFFFAOYSA-N n-(3-acetylphenyl)acetamide Chemical compound CC(=O)NC1=CC=CC(C(C)=O)=C1 AFZTYHRVDOKRKV-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WJKMUGYQMMXILX-UHFFFAOYSA-N 2-trimethylsilylacetonitrile Chemical compound C[Si](C)(C)CC#N WJKMUGYQMMXILX-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- JJIQMLCKWSALDB-UHFFFAOYSA-N n-ethyl-n-(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)acetamide Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC=C3N=CC=2)=C1 JJIQMLCKWSALDB-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000004622 sleep time Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of zaleplon.
- Zaleplon chemical name N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, is an American A new type of pyrazolopyrimidine sedative-hypnotic drug developed by Wyeth-Ayerst. In March 1999, the European Union approved zaleplon for the treatment of insomnia, and in August 1999, the US FDA approved zaleplon for adult insomnia. First launched in Denmark and Sweden in July 1999.
- Zaleplon is a full agonist of benzodiazepine ⁇ 1 receptors, with short half-life, good curative effect, few side effects and no psychosis. It is mainly used for short-term treatment of adult insomnia, which can make insomnia patients fall asleep quickly, shorten the time to fall asleep, prolong the sleep time, and reduce the number of awakenings. As the 21st century enters the 1920s, people's work and life rhythms continue to accelerate, and there will be more and more insomniacs, and the demand for sedative-hypnotics will also increase year by year. Therefore, Zaleplon has a relatively broad market prospect.
- Zaleplon has the following chemical structural formula:
- the purpose of the present invention is to overcome the above-mentioned deficiencies of the prior art, and provide a preparation method of zaleplon with short route, simple and cheap raw materials, simple and convenient operation, no transition metal catalysis and suitable for industrial production.
- the present invention adopts the following technical scheme for realizing the above-mentioned object, a kind of preparation method of zaleplon, is characterized in that concrete steps are:
- Step S1 Using m-nitrobenzaldehyde 1, 3-amino-4-cyanopyrazole 2 and triethylamine as raw materials, in the presence of an iodine reagent and an oxidant, 7-(3-nitrophenyl)pyridine is prepared Azole[1,5-a]pyrimidine-3-carbonitrile 3, its synthetic route is:
- the iodine reagent is ammonium iodide, N-iodosuccinimide, elemental iodine or tetrabutylammonium iodide, the oxidant is di-tert-butyl peroxide or dicumyl peroxide, and the solvent is toluene, Chlorobenzene, 1,4-dioxane, acetonitrile or tetrahydrofuran;
- Step S2 Compound 4 is obtained by one-pot reductive acetylation of 7-(3-nitrophenyl)pyrazo[1,5-a]pyrimidine-3-carbonitrile 3 with iron powder and glacial acetic acid.
- the synthetic route is as follows:
- Step S3 Compound 4 is ethylated with bromoethane to obtain compound 5, the target product Zaleplon, and its synthetic route is:
- the molar ratio of described m-nitrobenzaldehyde 1, 3-amino-4-cyanopyrazole 2, triethylamine, ammonium iodide and di-tert-butyl peroxide is 1:1:2: 1:3, the charging ratio of described m-nitrobenzaldehyde 1 and solvent is 1mmol:4mL.
- the preparation method of zaleplon of the present invention adopts simple and cheap m-nitrobenzaldehyde and triethylamine as raw materials, and adopts a one-pot series reaction without transition metal catalysis.
- the core skeleton of zaleplon is constructed with high efficiency and selectivity, thereby avoiding the generation of isomers, reducing the generation of by-products, improving the yield of the target product, and reducing the synthesis cost; after a simple nitro reduction modification , to prepare zaleplon.
- the whole preparation route is short, the reaction conditions are mild, the operation is simple, and it is suitable for industrial production.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种扎来普隆的制备方法,属于药物化学技术领域。本发明采用简单廉价的间硝基苯甲醛和三乙胺为原料,通过无过渡金属催化的一锅串联反应,高效高选择性构筑扎来普隆的核心骨架,从而规避异构体的产生,降低了副产物的生成,提高了目标产物的产率,降低了合成成本;后经过简单的硝基还原修饰,制备扎来普隆。整条路线简短,反应条件温和,操作简便,适合于工业化生产。
Description
本发明属于药物化学技术领域,具体涉及一种扎来普隆的制备方法。
扎来普隆(Zaleplon),化学名为N-[3-(3-氰基吡唑并[1,5-a]嘧啶-7-基)苯基]-N-乙基乙酰胺,是美国惠氏(Wyeth-Ayerst)公司研制的新型吡唑并嘧啶类镇静催眠药。1999年3月欧盟批准扎来普隆用于治疗失眠症,1999年8月美国FDA批准扎来普隆用于成人失眠症。1999年7月在丹麦和瑞典首次上市。扎来普隆作为一种已经应用于临床的第三代非苯二氮卓类镇静催眠药,是苯二氮卓ω1受体的完全激动剂,具有半衰期短,疗效好,副作用少、无精神依赖性等特点,主要用于成人失眠的短期治疗,可以使失眠病人很快入睡,缩短入睡时间,延长睡眠时间,减少觉醒的次数。随着21世纪进入20年代,人们工作和生活节奏的不断加快,失眠症患者将会越来越多,镇静催眠药的需求量也将逐年增加,因此扎来普隆具有较为广阔的市场前景。
扎来普隆具有如下化学结构式:
在已公开的扎来普隆的制备方法中,1986美国专利US4626538报道,以N-(3-乙酰基苯基)乙酰胺为原料,与N,N-二甲基甲酰胺二甲缩醛缩合;然后在氩气保护下,与氢化钠混合搅拌,冰浴冷却下滴加碘乙烷进行乙基化反应;最后一步在冰醋酸中与等摩尔的3-氨基-4-氰基吡唑进行环合反应即可得到扎来普隆。本合成路线步骤短,但操作比较繁琐,成环反应的区域选择性较差(有异构体生成)。
尽管后续不断有报道进行完善性研究,但没有突破成环反应的局限性,例如中国药科大学的尤启冬教授所报道的制备方法(中国药师,2002,5,265-266),只是将起始原料往前推到了苯乙酮,其经过硝化、还原、乙酰化转化为N-(3-乙酰基苯基)乙酰胺,虽然原料更加简单,但延长了合成路线使总收率较低,仍没有解决成环反应中区域选择性的问题,因而不利于大规模生产。
Boruah等人(RSCAdv.,2014,4,24001-24006)报道了以3-溴-3-(3-硝基苯基)丙烯醛和3-氨基-4-氰基吡唑为原料,醋酸钯催化,三苯基膦为配体,碳酸钾为碱在微波条件下,通过偶联反应先构建吡唑并嘧啶稠环以规避异构体的产生,但是其使用了昂贵的钯催化剂,从而导致反应液的后续处理程序复杂和成本高,而且所使用的原料3-溴-3-(3-硝基苯基)丙烯醛需要预制备。
2020年中国专利CN107973800报道了将N-乙基-N-(3-(吡唑并[1,5-a]嘧啶-7-基)苯基)乙酰胺与三甲基硅乙腈在含有吖啶盐催化剂的反应溶剂中进行光照反应,直接实现氰化反应制备扎来普隆,虽然该制备路线短,得率高,但所使用的原料N-乙基-N-(3-(吡唑并[1,5-a]嘧啶-7-基)苯基)乙酰胺需要多步预制备。
发明内容
本发明的目的在于克服上述现有技术的不足,提供了一种路线简短、原料简单廉价、操作简便、无过渡金属催化且适合于工业生产的扎来普隆的制备方法。
本发明为实现上述目的采用如下技术方案,一种扎来普隆的制备方法,其特征在于具体步骤为:
步骤S1:以间硝基苯甲醛1、3-氨基-4-氰基吡唑2和三乙胺为原料,在碘试剂和氧化剂存在下,制得7-(3-硝基苯基)吡唑[1,5-a]嘧啶-3-腈3,其合成路线为:
所述碘试剂为碘化铵、N-碘代丁二酰亚胺、单质碘或四丁基碘化铵,氧化剂为二叔丁基过氧化物或过氧化二异丙苯,溶剂为甲苯、氯苯、1,4-二氧六环、乙腈或四氢呋喃;
步骤S2:将7-(3-硝基苯基)吡唑[1,5-a]嘧啶-3-腈3通过铁粉和冰醋酸一锅还原乙酰化得到化合物4,其合成路线为:
步骤S3:将化合物4通过溴乙烷乙基化得到化合物5即目标产物扎来普隆,其合成路线为:
进一步优选,所述间硝基苯甲醛1、3-氨基-4-氰基吡唑2、三乙胺、碘化铵与二叔丁基过氧化物的投料摩尔比为1:1:2:1:3,所述间硝基苯甲醛1与溶剂的投料配比为1mmol:4mL。
本发明与现有技术相比具有以下优点和有益效果:本发明扎来普隆的制备方法采用简单廉价的间硝基苯甲醛和三乙胺为原料,通过无过渡金属催化的一锅串联反应,高效高选 择性构筑扎来普隆的核心骨架,从而规避异构体的产生,降低了副产物的生成,提高了目标产物的产率,降低了合成成本;后经过简单的硝基还原修饰,制备扎来普隆。另外,所述制备整条路线简短,反应条件温和,操作简便、适合于工业化生产。
以下通过实施例对本发明的上述内容做进一步详细说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
化合物3的制备
在35mL密封管中加入间硝基苯甲醛1(75.5mg,0.5mmol)、3-氨基-4-氰基吡唑2(54mg,0.5mmol)、三乙胺(101mg,1mmol)、碘化铵(72.5mg,0.5mmol)、二叔丁基过氧化物(219mg,1.5mmol)和甲苯(2mL),然后置于130℃油浴中搅拌反应10h。加入50mL水淬灭反应,用乙酸乙酯萃取(50mL×3),之后有机相用质量浓度为10%的Na
2S
2O
3溶液和饱和食盐水依次洗涤,无水硫酸钠干燥。过滤,旋干,过硅胶柱分离(石油醚/乙酸乙酯=3/1,v/v)得到黄色固体产物化合物3(114mg,86%)。该化合物的表征数据如下:
1H NMR(400MHz,DMSO-d
6):δ(ppm)8.97(d,J=1.6Hz,1H),8.95(d,J=4.8Hz,1H),8.88(s,1H),8.48(dd,J=8.0,2.0Hz,2H),7.92(t,J=8.0Hz,1H),7.72(d,J=4.4Hz,1H);
13C NMR(100MHz,DMSO-d
6):δ(ppm)153.9,150.9,147.5,147.4,145.3,136.2,130.9,130.4,126.2,124.8,113.3,111.3,81.7;HRMS(ESI):m/z[M+H]
+calcd for C
13H
8N
5O
2:266.0673;found:266.0674。
实施例2
化合物4的制备
在三颈瓶中投入铁粉(184.8mg,3.3mmol)和冰乙酸(20mL),搅拌加热至回流,酸化10min,滴加化合物3(265mg,1mmol)的冰醋酸(25mL)溶液。滴加完成后,继续回流4h。 加入50mL水淬灭反应,用乙酸乙酯萃取(50mL×3),之后有机相用饱和食盐水洗涤,无水硫酸钠干燥。过滤,旋干,干燥得白色固体化合物4(230mg,83%)。该化合物的表征数据如下:
1H NMR(400MHz,DMSO-d
6):δ(ppm)10.25(s,1H),8.89(d,J=4.4Hz,1H),8.86(s,1H),8.32(t,J=1.8Hz,1H),7.85–7.81(m,1H),7.70–7.67(m,1H),7.54(t,J=8.0Hz,1H),7.50(d,J=4.8Hz,1H),2.08(s,3H);
13C NMR(100MHz,DMSO-d
6):δ(ppm)168.7,153.8,151.1,147.5,147.3,139.4,129.9,129.1,124.3,122.0,119.9,113.5,110.7,81.4,24.0;HRMS(ESI):m/z[M+Na]
+calcd for C
15H
11N
5NaO:300.0856;found:300.0854。
实施例3
化合物5的制备
在充满氮气的三颈瓶中投入氢化钠(58mg,2.4mmol)和无水DMF(2mL),在冰水浴中搅拌,滴加化合物4(110.8mg,0.4mmol)的DMF(6mL)溶液,滴加完成后反应5min,滴加溴乙烷(436mg,4mmol),继续在冰水浴中搅拌30min。用乙酸乙酯萃取(50mL×3),之后有机相用饱和食盐水洗涤,无水硫酸钠干燥。过滤,旋干,干燥得白色固体化合物5(103.7mg,85%)。该化合物的表征数据如下:
1H NMR(400MHz,DMSO-d
6):δ(ppm)8.92(d,J=4.4Hz,1H),8.87(d,J=0.4Hz,1H),8.09(d,J=7.6Hz,1H),8.04(s,1H),7.71(t,J=7.8Hz,1H),7.67(d,J=4.4Hz,1H),7.61(d,J=7.2Hz,1H),3.70(q,J=6.8Hz,2H),1.81(s,3H),1.03(t,J=6.8Hz,3H);
13C NMR(100MHz,DMSO-d
6):δ(ppm)168.5,153.8,151.1,147.3,146.6,142.6,131.4,130.7,129.9,129.7,129.0,113.5,111.0,81.4,43.1,22.8,12.9;HRMS(ESI):m/z[M+Na]
+calcd for C
17H
15N
5NaO:328.1169;found:328.1171。
以上实施例描述了本发明的基本原理、主要特征及优点,本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明原理的范围下,所作的任何修改、等同替代和改进等,均应包含在本发明保护的范围内。
Claims (2)
- 根据权利要求1所述的扎来普隆的制备方法,其特征在于:所述间硝基苯甲醛1、3-氨基-4-氰基吡唑2、三乙胺、碘化铵与二叔丁基过氧化物的投料摩尔比为1:1:2:1:3,所述间硝基苯甲醛1与溶剂的投料配比为1mmol:4mL。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105622615A (zh) * | 2015-12-30 | 2016-06-01 | 上海天慈国际药业有限公司 | 一种合成扎莱普隆的新方法 |
CN109912606A (zh) * | 2019-04-16 | 2019-06-21 | 新乡医学院 | 一种嘧啶并吲唑类化合物的合成方法 |
CN112724150A (zh) * | 2021-02-18 | 2021-04-30 | 新乡医学院 | 一种扎来普隆的制备方法 |
CN112778317A (zh) * | 2021-02-18 | 2021-05-11 | 安徽工业大学 | 一种[1,2,4]三氮唑并[1,5-a]嘧啶类化合物的合成方法 |
CN112939986A (zh) * | 2021-02-18 | 2021-06-11 | 新乡医学院 | 一种吡唑并嘧啶类化合物的合成方法 |
CN112939987A (zh) * | 2021-02-18 | 2021-06-11 | 新乡医学院 | 一种茚地普隆中间体的制备方法 |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105622615A (zh) * | 2015-12-30 | 2016-06-01 | 上海天慈国际药业有限公司 | 一种合成扎莱普隆的新方法 |
CN109912606A (zh) * | 2019-04-16 | 2019-06-21 | 新乡医学院 | 一种嘧啶并吲唑类化合物的合成方法 |
CN112724150A (zh) * | 2021-02-18 | 2021-04-30 | 新乡医学院 | 一种扎来普隆的制备方法 |
CN112778317A (zh) * | 2021-02-18 | 2021-05-11 | 安徽工业大学 | 一种[1,2,4]三氮唑并[1,5-a]嘧啶类化合物的合成方法 |
CN112939986A (zh) * | 2021-02-18 | 2021-06-11 | 新乡医学院 | 一种吡唑并嘧啶类化合物的合成方法 |
CN112939987A (zh) * | 2021-02-18 | 2021-06-11 | 新乡医学院 | 一种茚地普隆中间体的制备方法 |
Non-Patent Citations (2)
Title |
---|
GAO QINGHE, HAN XINYA, TONG PEIYUAN, ZHANG ZHIANG, SHEN HAOTIAN, GUO YANRONG, BAI SUPING: "Aerobic α,β-C(sp 3 )–H Bond Difunctionalization and C–N Bond Cleavage of Triethylamine: Difunctional Ammonium Iodide Enabling the Regioselective Synthesis of 4-Arylpyrimido[1,2- b ]indazoles", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 21, no. 15, 2 August 2019 (2019-08-02), US , pages 6074 - 6078, XP055960575, ISSN: 1523-7060, DOI: 10.1021/acs.orglett.9b02218 * |
SHEKARRAO KOMMURI ET AL.: "Microwave-assisted Palladium Mediated Efficient Synthesis of Pyrazolo[3, 4-b]pyridines, Pyrazolo[3, 4-b]quinolines, Pyrazolo[1, 5-a]pyrimidines and Pyrazolo[1, 5-a]quinazolines", RSC ADVANCES, vol. 4, no. 46, 5 June 2014 (2014-06-05), XP055801520, ISSN: 2046-2069, DOI: 10.1039/C4RA02865A * |
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