JP2019131483A - エボジアミンの製造方法 - Google Patents
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- TXDUTHBFYKGSAH-SFHVURJKSA-N Evodiamine Chemical compound C1=CC=C2N(C)[C@@H]3C(NC=4C5=CC=CC=4)=C5CCN3C(=O)C2=C1 TXDUTHBFYKGSAH-SFHVURJKSA-N 0.000 title claims abstract description 53
- HMXRXBIGGYUEAX-SFHVURJKSA-N Evodiamine Natural products CN1[C@H]2N(CCc3[nH]c4ccccc4c23)C(=O)c5ccccc15 HMXRXBIGGYUEAX-SFHVURJKSA-N 0.000 title claims abstract description 53
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 238000010438 heat treatment Methods 0.000 claims abstract description 21
- 150000007530 organic bases Chemical class 0.000 claims abstract description 19
- 239000003377 acid catalyst Substances 0.000 claims abstract description 14
- 150000002148 esters Chemical class 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 claims description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- KJMRWDHBVCNLTQ-UHFFFAOYSA-N N-methylisatoic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)N(C)C2=C1 KJMRWDHBVCNLTQ-UHFFFAOYSA-N 0.000 claims description 14
- 239000007795 chemical reaction product Substances 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000006482 condensation reaction Methods 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 abstract description 12
- 230000002829 reductive effect Effects 0.000 abstract description 9
- 239000000376 reactant Substances 0.000 abstract 1
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HJGHAQFHGFDSCJ-UHFFFAOYSA-N 7h-pyrimido[5,4-c]carbazole Chemical group C1=NC=NC2=C3C4=CC=CC=C4NC3=CC=C21 HJGHAQFHGFDSCJ-UHFFFAOYSA-N 0.000 description 1
- 241001079251 Euodia Species 0.000 description 1
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Chemical compound C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- IIGJYLXJNYBXEO-UHFFFAOYSA-N dimethoxymethanol Chemical compound COC(O)OC IIGJYLXJNYBXEO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- -1 for example Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- ZASDXSYSMJAHCJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical compound C(OC(C)(C)C)(O)=O.C(OC(C)(C)C)(O)=O ZASDXSYSMJAHCJ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
下記式(2)で表される化合物とオルトギ酸エステルを、非還元性の酸触媒の存在下で加熱して反応させる工程と、
得られた反応物を有機塩基の存在下で加熱する工程とを含むことを特徴とするエボジアミンの製造方法。
当該工程において、オルトギ酸エステルとしては、ホルミル化剤として用いることができるものであればよく、例えば、オルトギ酸トリメチル、オルトギ酸トリエチル、ジメチルホルムアミドジメチルアセタール等が挙げられ、なかでも、オルトギ酸トリメチル、オルトギ酸トリエチルが好ましい。
式(2)で表される化合物とオルトギ酸エステルを非還元性の酸触媒の存在下で加熱して反応させる工程だけでも目的物であるエボジアミンを生成し得るが、収率が低かった。本発明においては、得られた反応物を有機塩基の存在下で加熱することによって、エボジアミンを高い収率で製造することができる。当該工程は、上記のとおり、還流によって行うことが好ましい。
トリプタミン( 2.9g、17.8mmol)、N−メチルイサト酸無水物( 3.2g、18mmol)をTHF溶媒中で縮合させ、式(2)で表される化合物Benzamide, N-[2-(1H-indol-3-yl)ethyl]-2-(methylamino)-を得た。
1H-NMR (CDCl3-d6, 600 MHz) δ2.85 (3H, s), 3.08 (2H, t, J = 6.6Hz), 3.75 (2H, dd, J = 12.6, 6.6Hz), 6.11 (1H, brs), 6.50 (1H, td, J = 7.8, 0.6Hz), 6.64 (1H, d, J = 8.4Hz), 7.07 (1H, d, J = 2.4Hz), 7.12-7.15 (2H, m), 7.22 (1H, td, J = 8.4, 1.2Hz), 7.28 (1H, ddd, J = 8.4, 7.2, 1.2Hz), 7.39 (1H, d, J = 8.4Hz), 7.46 (1H, brs), 7.65 (1H, dd, J = 7.8, 0.6Hz)
前記参考例1で得た式(2)で表される化合物66.4mgおよびオルトギ酸トリメチル(10mL)の混合液に酢酸(10mL)を添加し、100℃で24時間攪拌した。冷却後、得られた反応混液を減圧濃縮し、少量のエボジアミンを得た。(収率:10%)
比較例1で酢酸の代わりにパラトルエンスルホン酸を使用した場合、エボジアミンは得られず、反応が進まなかった。
前記参考例1で得た式(2)で表される化合物64.6mgおよびオルトギ酸トリメチル(0.5mL)、のギ酸(0.5mL)混合液を110℃で18時間撹拌した場合、冷却後、得られた反応混液を減圧下蒸発させた後に、ピリジンに溶解させ120℃で2時間撹拌し、冷却後得られた反応混液を減圧濃縮し、シリカゲルカラムクロマトグラフィーで精製して下記の化合物が収率67%で得られた。
前記参考例1で得た式(2)で表される化合物51.3 mgおよびオルトギ酸トリメチル(0.5mL)の酢酸(0.5mL)混合液を、100℃で26時間撹拌した。冷却後、得られた反応混液に、ピリジン(0.5mL)を加え、さらに、125℃で2時間撹拌した。冷却後得られた反応混液を減圧濃縮し、シリカゲルカラムクロマトグラフィーで精製し、エボジアミンが61%の収率で得られた。
前記参考例1で得た式(2)で表される化合物50.8mgおよびオルトギ酸トリエチル(0.25mL)の1,2−DCE(0.5mL)懸濁液にSc(OTf)3(2mol%)を室温中で添加し、125℃で20時間撹拌した。冷却後、得られた反応混液に、ピリジン(0.5mL)を加え、さらに、125℃で2時間撹拌した。冷却後得られた反応混液を減圧濃縮し、シリカゲルカラムクロマトグラフィーで精製し、エボジアミンが57%の収率で得られた。
トリプタミン(3.0g、18.7mmol)、N−メチルイサト酸無水物(3.3g、18.6mmol)、及び、オルトギ酸トリメチル(10mL)の懸濁液を100℃で2時間攪拌し、式(2)で表される化合物が得られていることをシリカゲル薄層クロマトグラフィー(TLC)プレートで確認した。冷却後、得られた反応混液に酢酸(10mL)を添加し、100℃で3時間攪拌した。冷却後、得られた反応混液を減圧濃縮し、トルエン(50mL×2)で共沸し、その残渣をピリジン(20mL)で溶解した。その後、得られた反応混液を125℃で3時間攪拌した。酢酸エチル(150mL)を添加した後、沈殿した目的物を少量のメタノールと共に濾過して回収し、エボジアミンを得た(この工程は2回繰り返した)。エボジアミンの収量は4.6g(4.4g+0.2g)(15.2mmol)であり、収率は82%であった。
1H-NMR spectrum of evodiamine (600MHz, DMSO-d6) δ2.80 (1H, dd, J = 4.2, 15.0Hz), 2.88-2.95 (1H, m), 3.21 (1H, ddd, J = 4.8, 12.0, 12.6Hz), 4.63 (1H, dd, J = 11.4, 12.6Hz), 6.13 (1H, s), 6.97 (1H, td, J = 7.8, 0.6Hz), 7.00 (1H, td, J = 7.8, 0.6Hz), 7.06 (1H, d, J = 7.8Hz), 7.11 (1H, td, J = 7.2, 0.6Hz), 7.36 (1H, d, J = 7.8Hz), 7.47 (1H, dd, J = 1.8, 7.2Hz), 7.49 (1H, dd, J = 1.8, 7.8Hz), 7.80 (1H, dd, J = 1.2, 7.8Hz), 11.07 (1H, s)
Claims (6)
- 前記式(2)で表される化合物を、トリプタミンとN−メチルイサト酸無水物をオルトギ酸エステル中で縮合反応させることによって合成する請求項1記載のエボジアミンの製造方法。
- 前記得られた反応物を有機塩基の存在下で加熱する工程を還流によって行う請求項1又は2記載のエボジアミンの製造方法。
- 前記非還元性の酸触媒が、酢酸及びトリフルオロメタンスルホン酸スカンジウムから選ばれる少なくとも1種である請求項1〜3のいずれか一項記載のエボジアミンの製造方法。
- 前記有機塩基が、ピリジン、トリエチルアミン及びN,N−ジイソプロピルエチルアミンから選ばれる少なくとも1種である請求項1〜4のいずれか一項記載のエボジアミンの製造方法。
- 前記得られた反応物を有機塩基の存在下で加熱する工程において、前記得られた反応物を乾固した後の残渣を加熱する請求項1〜5のいずれか一項記載のエボジアミンの製造方法。
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CN115141199A (zh) * | 2022-06-28 | 2022-10-04 | 江西师范大学 | 一种合成吴茱萸次碱的新方法 |
CN115141199B (zh) * | 2022-06-28 | 2023-04-07 | 江西师范大学 | 一种合成吴茱萸次碱的新方法 |
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