CN113480523A - 匹莫苯丹的制备方法 - Google Patents
匹莫苯丹的制备方法 Download PDFInfo
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- CN113480523A CN113480523A CN202110696299.9A CN202110696299A CN113480523A CN 113480523 A CN113480523 A CN 113480523A CN 202110696299 A CN202110696299 A CN 202110696299A CN 113480523 A CN113480523 A CN 113480523A
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- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229960002164 pimobendan Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 6
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- VFIKPDSQDNROGM-UHFFFAOYSA-N 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C1=CC(OC)=CC=C1B1OC(C)(C)C(C)(C)O1 VFIKPDSQDNROGM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical group C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 1
- SVNHZTWHIADGMX-UHFFFAOYSA-N cyclopenta-1,3-diene [cyclopenta-2,4-dien-1-yl(phenyl)phosphoryl]benzene iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.O=P(c1ccccc1)(c1ccccc1)[c-]1cccc1 SVNHZTWHIADGMX-UHFFFAOYSA-N 0.000 claims 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 1
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 5
- 238000006396 nitration reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WXSDHOPIGKDWTF-UHFFFAOYSA-N 3-(3,4-diaminophenyl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C1=CC=C(N)C(N)=C1 WXSDHOPIGKDWTF-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 229960001413 acetanilide Drugs 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000013341 scale-up Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- REBZXOIBOIJEAU-UHFFFAOYSA-N 3-chloro-2-methylpropanoyl chloride Chemical compound ClCC(C)C(Cl)=O REBZXOIBOIJEAU-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 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
- 230000024883 vasodilation Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical class CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- ANBGTJZLSYGADN-UHFFFAOYSA-N 4-(4-acetamido-3-nitrophenyl)-3-methyl-4-oxobutanoic acid Chemical compound C(C)(=O)NC1=C(C=C(C=C1)C(C(CC(=O)O)C)=O)[N+](=O)[O-] ANBGTJZLSYGADN-UHFFFAOYSA-N 0.000 description 1
- OLJROCDVDZVLNU-UHFFFAOYSA-N 4-(4-acetamidophenyl)-3-methyl-4-oxobutanoic acid Chemical compound OC(=O)CC(C)C(=O)C1=CC=C(NC(C)=O)C=C1 OLJROCDVDZVLNU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940122434 Calcium sensitizer Drugs 0.000 description 1
- 102000002585 Contractile Proteins Human genes 0.000 description 1
- 108010068426 Contractile Proteins Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical class [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 102000010861 Type 3 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037543 Type 3 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及匹莫苯丹的制备新工艺。具体为化合物式I(6‑(2‑溴‑1H‑苯并[d]咪唑‑6‑基)‑5‑甲基‑4,5‑二氢哒嗪‑3(2H)‑酮)在Pd催化剂的作用下，与化合物式II(对甲氧基苯硼酸或者对甲氧基苯硼酸频那醇酯)发生Suzuki偶联反应，实现匹莫苯丹的制备。
Description
技术领域
本发明涉及匹莫苯丹的制备。
背景技术
匹莫苯丹是由德国Boehringer Ingelheim公司研制开发,于1994年首次在日本上市的一种具有血管扩张作用的强心药,属于磷酸二酯酶抑制剂,临床上主要用于心衰病的治疗。该化合物是具有钙敏化作用及III型磷酸酶抑制剂作用的强心扩张剂化合物,作用机理区别于传统的强心药,其正性肌力效应主要归因于增强心肌收缩蛋白对Ca2+的敏感性和对磷酸二酯酶III(PDE III)的抑制作用,是第一个上市的钙敏化剂类药物。研究表明,该药具有较强的血管扩张作用以及抗血小板聚集作用,几乎无副作用,也可治疗慢性心功能不全和狭心症,还可预防和治疗动脉血栓症。另外,大量临床试验还表明,心力衰竭患者长期口服方式服用匹莫苯丹可有效改善运动耐受性及生活品质。匹莫苯丹的化学名为:4,5-二氢-6-[2-(4-甲氧基苯基)-1H-苯并咪唑-5-基]-5-甲基-3(2H)-哒嗪酮,具有如下化学结构式：
目前公开报道的制备匹莫苯丹的专利文献较多。早在1982年Austel等人(US4361563)报道了以氯苯为起始原料的合成路线，经付-克反应、硝化反应、羰基的α位溴化、丙二酸酯亲核取代、KOH水解、加热脱羧、氨化、酯化、对甲氧基苯甲酰氯酰化、水和肼环合、氢化、环合等步骤第一次报道了匹莫苯丹的全合成。该路线路线长(共12步反应)，且该路线存在氨化反应需高压釜、溴化时需用腐蚀性很强的溴等缺点，因此工业化生产受到局限。相关合成路线如下所示：
朴日阳和段永熙等人(中国药物化学杂志，1994,4,41)开发了以乙酰苯胺为原料的合成路线。该路线通过付-克酰基化反应、Mannich反应、季胺盐化、腈化取代、硝化等10步反应完成了匹莫苯丹的合成。虽然该路线相比US 4361563路线有所缩短，但是由于反应过程中涉及到使用剧毒的KCN，因而不适用于放大生产。1998年宫平等人对朴日阳的合成路线进行了优化(沈阳药科大学学报，1998,15,125)。朴日阳报道的工艺具体合成路线如下所示：
王思思等人(中国药物化学杂志，1997,7,185)综合了专利US 4361563和朴日阳等人的工艺，报道了以乙酰苯胺为原料，通过付-克酰基化反应、溴代反应、丙二酸二乙酯亲核取代反应等9步反应制备匹莫苯丹的合成路线。该路线虽然步骤有所缩短，但是由于反应过程中不仅同样涉及到使用溴等腐蚀性强的试剂,而且使用工业化生产难以控制的NaH，因而工业化生产同样受到局限。该工艺具体合成路线如下所示：
许佑君等人(合成化学，1999,7,194)报道了一条合成匹莫苯丹的路线。该路线同样使用乙酰苯胺作为起始原料，首先通过和3-氯-2-甲基丙酰氯进行付-克酰基化反应，一步得到4-(3- 氯-2-甲基丙酰基)乙酰苯胺，后者再经过腈基取代反应、硝化反应、Zn/NH4Cl还原反应等实现匹莫苯丹的合成。该路线虽然合成步骤短，但是由于3-氯-2-甲基丙酰氯商业化不易大量采购、且反应过程中同样涉及到使用剧毒的KCN,因而工业化生产受到限制。该工艺具体合成路线如下所示：
专利CN201710595181.0报道了匹莫苯丹关键中间体6-(3,4-二氨基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮的制备方法，该方法以4-(4-乙酰氨基苯基)-3-甲基-4-氧代丁酸为起始物料，首先通过硝化反应制备得到4-(4-乙酰氨基-3-硝基苯基)-3-甲基-4-氧代丁酸，然后使用水合肼/钯碳条件在加热条件下同时还原硝基和进行二氢哒嗪环形成，得到6-(3,4-二氨基苯基) -5-甲基-4,5-二氢哒嗪-3(2H)-酮，随后6-(3,4-二氨基苯基)-5-甲基-4,5-二氢哒嗪-3(2H) -酮和对甲氧基苯甲醛进行缩合，完成匹莫苯丹的制备。该方法的技术路线如下：
综合上述已公开报道的合成匹莫苯丹的方法，US4361563专利、朴日阳报道的合成路线、王思思报道的合成路线以及许佑君等报道的合成路线分别使用了工业上大量使用受到局限的 Br2,KCN,硝化反应、NaH/Br2，因此这些路线都不适合工业化放大生产。为此，开发一条适合工业化放大生产的匹莫苯丹合成路线对于匹莫苯丹药物的产业化尤其重要。
发明内容
本发明的关键在于新开发一条适合工业化生产匹莫苯丹的方法，合成路线如下所示。
本发明的合成方法是化合物式I(6-(2-溴-1H-苯并[d]咪唑-6-基)-5-甲基-4,5-二氢哒嗪 -3(2H)-酮)在Pd催化剂的作用下，与化合物式II(对甲氧基苯硼酸或者对甲氧基苯硼酸频那醇酯)发生Suzuki偶联反应，实现匹莫苯丹的制备。
该Suzuki偶联反应所使用的Pd催化基包括Pd(OAc)2、Pd(PPh3)4、PdCl2、PdCl2(PPh3)2、 PdCl2(dppf)·CH2Cl2、Pd2(dba)3、Pd2(dba)3·CHCl3和(t-Bu3P)2Pd中的一种或多种；其中，dppf 代表双(二苯基瞵基)二茂铁；dba代表二亚苄基丙酮；OAc表示醋酸根；
该Suzuki偶联反应所使用的溶剂包括异丙醇、苯、四氢呋喃、乙二醇二甲醚、乙腈、甲基吡咯烷酮、二氧六环、甲苯、乙醇和N,N-二甲基甲酰胺中的一种或多种；
该Suzuki偶联反应所使用的碱包括N,N-二甲基甲酰胺、NaHCO3、KF、KHCO3、K2CO3、Na2CO3、Et3N、CsF、Cs2CO3、NaOH、KOH、LiOH、(iPr)2NEt、Et3N和K3PO4中的一种或多种。
本发明描述的匹莫苯丹的制备工艺，操作简单，反应条件温和。
具体实施方式
通过下面的实施例可以更具体的理解本发明，但其是举例说明而不是限制本发明的范围。
实施例
制备匹莫苯丹反应瓶中加入化合物式I(100g,325.6mmol)和Cs2CO3(265.2g,814mmol,2.5eq),氮气保护下,向反应体系加入Dioxane(5.0L)和DMF(2.0L)。加入完毕后体系搅拌下室温抽真空脱气1小时，然后氮气保护下向反应体系中加入对甲氧基苯硼酸频哪醇酯(152.4g, 651.0mmol,2.0eq)和PdCl2(PPh3)2(22.9g,32.6mmol,0.1eq)。加入完毕后体系使用氮气置换3次。体系加热至80-85℃反应12小时，然后自然降温至室温。过滤，滤液减压浓缩去除有机溶剂。残余物加入DMF(2.0L)，缓慢升温至体系溶清，然后维持温度向体系中缓慢滴加H2O(3.0L),滴加完毕后体系搅拌6小时，体系降温至55-60℃，维持体系55-60℃搅拌2小时，过滤，所得固体减压干燥，得匹莫苯丹(92.5g,84.9％)。1H NMR (600MHz,DMSO-D6)δ1.14(d,J＝7.2Hz,3H),2.29(d,J＝16.2Hz,1H),2.76(dd,J＝ 16.8,6.6Hz,1H),3.52(m,1H),3.87(s,3H),7.15(m,2H),7.63(d,J＝8.4Hz,1H),7.75(d, J＝8.4 Hz,1H),7.98(br,1H),8.18(m,2H),10.99(s,1H),12.95(br,1H)。
Claims (4)
1.一条制备匹莫苯丹的制备工艺，具体为化合物式I(6-(2-溴-1H-苯并[d]咪唑-6-基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮)在Pd催化剂的作用下，与化合物式II(对甲氧基苯硼酸或者对甲氧基苯硼酸频那醇酯)发生Suzuki偶联反应，实现匹莫苯丹的制备。该工艺具有如下的合成路线。
2.权利要求1所示的方法，使用的催化剂包括Pd(PPh3)4、PdCl2(dppf)·CH2Cl2、Pd(OAc)2、PdCl2、PdCl2(PPh3)2、Pd2(dba)3、Pd2(dba)3·CHCl3和(t-Bu3P)2Pd中的一种或多种；其中，dba代表二亚苄基丙酮,dppf代表双(二苯基瞵基)二茂铁,OAc表示醋酸根；
3.权利要求1所示的方法，反应使用的溶剂包括四氢呋喃、异丙醇、苯、乙腈、乙二醇二甲醚、二氧六环、甲基吡咯烷酮、甲苯、乙醇和N,N-二甲基甲酰胺中的一种或多种；
4.权利要求1所示的方法，反应所使用的碱包括KOH、NaHCO3、KF、KHCO3、K3PO4、K2CO3、Na2CO3、Et3N、CsF、Cs2CO3、NaOH、LiOH、(iPr)2NEt和Et3N中的一种或多种。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016180472A1 (en) * | 2015-05-11 | 2016-11-17 | Kancera Ab | Benzimidazole derivates useful as inhibitors of mammalian histone deacetylase activity |
| CN107176948A (zh) * | 2017-07-20 | 2017-09-19 | 海门慧聚药业有限公司 | 匹莫苯丹的制备 |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016180472A1 (en) * | 2015-05-11 | 2016-11-17 | Kancera Ab | Benzimidazole derivates useful as inhibitors of mammalian histone deacetylase activity |
| CN107176948A (zh) * | 2017-07-20 | 2017-09-19 | 海门慧聚药业有限公司 | 匹莫苯丹的制备 |
Non-Patent Citations (2)
| Title |
|---|
| 王恩思: "新型强心药物匹莫苯的合成", 《中国药物化学杂志》 * |
| 赵乐凯 等: "匹莫苯丹的合成工艺研究进展", 《中国兽药杂志》 * |
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