CN114805170B - 一种新型赛洛多辛手性中间体的制备方法 - Google Patents
一种新型赛洛多辛手性中间体的制备方法 Download PDFInfo
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- CN114805170B CN114805170B CN202210069239.9A CN202210069239A CN114805170B CN 114805170 B CN114805170 B CN 114805170B CN 202210069239 A CN202210069239 A CN 202210069239A CN 114805170 B CN114805170 B CN 114805170B
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- ethyl acetate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- PNCPYILNMDWPEY-QGZVFWFLSA-N silodosin Chemical compound N([C@@H](CC=1C=C(C=2N(CCCO)CCC=2C=1)C(N)=O)C)CCOC1=CC=CC=C1OCC(F)(F)F PNCPYILNMDWPEY-QGZVFWFLSA-N 0.000 title abstract description 16
- 229960004953 silodosin Drugs 0.000 title abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 4
- JRTIUDXYIUKIIE-KZUMESAESA-N (1z,5z)-cycloocta-1,5-diene;nickel Chemical compound [Ni].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 JRTIUDXYIUKIIE-KZUMESAESA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000000543 intermediate Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000013110 organic ligand Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 2
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-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
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 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
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- AIVAIUMRPBQMLT-UHFFFAOYSA-N 3-acetylpentane-2,4-dione;nickel Chemical compound [Ni].CC(=O)C(C(C)=O)C(C)=O AIVAIUMRPBQMLT-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 102000019269 Alpha 1A adrenoceptor Human genes 0.000 description 1
- 108050006749 Alpha 1A adrenoceptor Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- UXRZLDREKITWRO-UHFFFAOYSA-N P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 UXRZLDREKITWRO-UHFFFAOYSA-N 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- ZXKWUYWWVSKKQZ-UHFFFAOYSA-N cyclohexyl(diphenyl)phosphane Chemical compound C1CCCCC1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZXKWUYWWVSKKQZ-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- OCMNCWNTDDVHFK-UHFFFAOYSA-L dichloronickel;1,2-dimethoxyethane Chemical compound Cl[Ni]Cl.COCCOC OCMNCWNTDDVHFK-UHFFFAOYSA-L 0.000 description 1
- IZWRXCGNSVOSAT-UHFFFAOYSA-L dichloronickel;diphenyl(propyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(CCC)C1=CC=CC=C1 IZWRXCGNSVOSAT-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- HFFHNJKBAYQARL-UHFFFAOYSA-N ditert-butyl(cyclohexyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1CCCCC1 HFFHNJKBAYQARL-UHFFFAOYSA-N 0.000 description 1
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+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 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明公开了一种赛洛多辛手性中间体的制备方法，所述中间体的结构式如式Ⅰ所示，该化合物可以作为中间体化合物，用于合成赛洛多辛。所述制备方法具有操作简单、成本低、收率高、产品光学纯度高、工艺稳定等特点，适合工业化生产。
Description
技术领域
本发明属于药物化学合成技术领域，具体涉及一种赛洛多辛手性中间体的制备方法。
背景技术
良性前例腺增生(BPH)是中老年男性常见病之一，在60岁或者以上老年人中有50％以上患有此病，而85岁以上的老年人中有90％以上患者。
赛洛多辛(Silodosin)，化学名：1-(3-羟丙基)-5-[(2R)-2-({2-(2,2,2-三氟乙氧基)苯氧基]乙基}氨基)丙基]-2,3-二氢-1H-吲哚-7-羧基酰胺，是一种高选择性的α1A-肾上腺素受体拮抗剂，用于治疗良性前列腺增生所致的排尿困难，最早由日本Kissei制药公司研发成功，于2006年5月在日本获得上市批准，随后在美国、欧洲也被获批上市。赛洛多辛结构中存在一个手性碳，起到药理活性的主要是R构型的结构，S构型结构的对映异构体作为杂质存在于赛洛多辛中，不仅会影响赛洛多辛的纯度，还可能会带来非治疗性的毒副作用，因此确定一种高光学纯度赛洛多辛或关键手性中间体的制备方法对有效控制赛洛多辛的质量有重要意义。
目前对于光学纯的赛洛多辛中间体的制备方法有很多，可以总结为三类：一是专利JP2002265444、WO2013056842、JP2002265444、CN101759627描述的通过拆分法来得到赛洛多辛手性中间体，该方法收率低，物料损耗大；二是专利JP2001199956、CN109305932、CN101993406A、描述的手性诱导方法，该方法使用手性辅剂贵，得到的中间体光学纯度不高等缺点；三是专利WO2016139773、WO2011030356、CN106045895A、CN103420893A、CN103554003A、KR20150066777、CN106045895描述与手性化合物对接来构建手性中心的方法，该方法得到的中间体的光学纯度直接来源于原料，但是需要多步反应来构建，收率低。
基于现有技术在合成赛洛多辛时，由于关键手性中间体合成工艺复杂，成本高而提出本发明。
发明内容
本发明的目的在于提供一种赛洛多辛手性中间体的新合成方法，该方法能够提高手性中间体的工业化可行性和稳定性，减少手性中间体的合成步骤，降低危险性和成本。
本发明提供了一种具有式Ⅰ结构中间体的制备方法，
该制备方法为在碱性条件、金属催化剂及有机配体催化下，将式Ⅱ与式Ⅲ进行偶联反应制备式Ⅳ，式Ⅳ脱去保护基R3制备化合物Ⅰ。
优选地，R1为羟基保护基，选自苄基或取代的苄基，苯甲酰基或取代的苯甲酰基。
更优选地，R1为苄基或苯甲酰基。
更优选地，R1为苯甲酰基。
优选地，R3为甲酸叔丁酯、甲酸苄酯或苄基。
更优选地，R3为甲酸叔丁酯。
优选地，R2选自Cl、Br、I或OTf，则R4为B(OH)2、Bpin、B(CH2)3或9-BBN。
优选地，R2选自B(OH)2、Bpin、B(CH2)3或9-BBN，则R4为Cl、Br、I或OTf。
优选地，所述的碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、磷酸钾、三乙胺、N,N-二异丙基乙胺、三乙烯二胺、1,8-二氮杂二环十一碳-7-烯、叔丁醇钠、叔丁醇钾、甲醇钠、乙醇钠及其组合。
优选地，金属催化剂选自金属钯催化剂如醋酸钯、四(三苯基膦)钯、氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、双三苯基磷二氯化钯、三(二亚苄基丙酮)二钯、三(二亚苄基丙酮)二钯-氯仿加合物；金属镍催化剂如1,3-双(二苯基膦丙烷)二氯化镍、二乙酰丙酮镍、氯化镍二甲氧基乙烷、双-(1,5-环辛二烯)镍、双(三苯基膦)氯化镍；金属铜催化剂如氯化亚铜、溴化亚铜、碘化亚铜及其组合。
优选地，所述有机配体选自三苯基膦、三环己基膦、二苯基环己基膦、4,5-双二苯基膦-9,9-二甲基氧杂蒽、2-二环己基膦-2',4',6'-三异丙基联苯、2-双环己基膦-2',6'-二甲氧基联苯、二叔丁基环己基膦、三(邻甲苯基)膦、2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯、1,2,3,4,5-五苯基-1'-(二叔丁基膦)二茂铁、1,1'-双(二苯基膦)二茂铁、2-叔丁基膦-2',4',6'-三异丙基联苯、N,N,N',N'-四甲基乙二胺、1,2-双(二苯基膦)乙烷、N,N'-二甲基乙二胺及其组合。
更优选地，所述有机配体为三环己基膦。
具体实施方式
以下结合实施例对本发明作进一步的详细描述，但并非对本发明的限制，凡依照本发明公开内容所作的任何本领域的等同替换，均属于本发明的保护范围。
实施例1化合物IV的制备
将10g II-1和8.9g III-1溶于100ml 1,4-二氧六环中，加入11g磷酸钾和1.9g[1,1'-双(二苯基膦基)二茂铁]二氯化钯，氮气置换3次，在氮气保护下，80℃下反应，TLC检测反应结束后，过滤，向滤液加入100ml，用100ml乙酸乙酯萃取，分液，水相再用乙酸乙酯洗三次(50ml*3)，有机相用无水硫酸钠干燥，浓缩，得到固体用乙酸乙酯和石油醚重结晶，得到9.6g白色固体，收率80％.
1H-NMR(300MHz,d6-MDSO):δ8.02(d,2H)；7.63(t,1H)；7.52(t,2H)；7.19(s,1H)；7.06(s,1H)；6.72(d,1H)；4.31(t,2H)；4.22-4.17(m,1H)；3.75(t,2H)；3.60(t,2H)；2.89(t,2H)；2.81(d,1H)；2.57(d,1H)；1.98-1.88(m,2H)；1.32(s,9H),1.10(s,3H).EIMS m/z464.3([M+H]+)。
实施例2化合物IV的制备
将10g II-1和8.9g III-1溶于100ml 1,4-二氧六环中，加入5.8g叔丁醇钾，1.5g三环己基膦和0.7g双-(1,5-环辛二烯)镍，氮气置换3次，在氮气保护下，90℃下反应，TLC检测反应结束后，过滤，向滤液加入100ml，用100ml乙酸乙酯萃取，分液，水相再用乙酸乙酯洗三次(50ml*3)，有机相用无水硫酸钠干燥，浓缩，得到固体用乙酸乙酯和石油醚重结晶，得到7.2g白色固体，收率60％。核磁与质谱与实施例1一致。
实施例3化合物IV的制备
将10g II-1和6.3g III-2溶于100ml 1,4-二氧六环中，加入11g磷酸钾和1.1g[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，氮气置换3次，在氮气保护下，80℃下反应，TLC检测反应结束后，过滤，向滤液加入100ml，用100ml乙酸乙酯萃取，分液，水相再用乙酸乙酯洗三次(50ml*3)，有机相用无水硫酸钠干燥，浓缩，得到固体用乙酸乙酯和石油醚重结晶，得到8.7g白色固体，收率72％。核磁与质谱与实施例1一致。
实施例4化合物IV的制备
将10g II-1和7.9g III-1溶于100ml 1,4-二氧六环中，加入6.4g碳酸钾和1.7g[1,1'-双(二苯基膦基)二茂铁]二氯化钯，氮气置换3次，在氮气保护下，90℃下反应，TLC检测反应结束后，过滤，向滤液加入100ml，用100ml乙酸乙酯萃取，分液，水相再用乙酸乙酯洗三次(50ml*3)，有机相用无水硫酸钠干燥，浓缩，得到固体用乙酸乙酯和石油醚重结晶，得到7.8g白色固体，收率65％。核磁与质谱与实施例1一致。
实施例5化合物IV的制备
将10g II-1和9.8g III-1溶于100ml 1,4-二氧六环中，加入7.9g碳酸钾和2.1g[1,1'-双(二苯基膦基)二茂铁]二氯化钯，氮气置换3次，在氮气保护下，90℃下反应，TLC检测反应结束后，过滤，向滤液加入100ml，用100ml乙酸乙酯萃取，分液，水相再用乙酸乙酯洗三次(50ml*3)，有机相用无水硫酸钠干燥，浓缩，得到固体用乙酸乙酯和石油醚重结晶，得到7.9g白色固体，收率60％。核磁与质谱与实施例1一致。
实施例6化合物IV的制备
将20g IV-4溶于200ml二氯甲烷中，加入40ml三氟乙酸，室温反应，TLC检测反应结束后，浓缩，随后加入200ml水喝200ml乙酸乙酯，萃取，水相用乙酸乙酯洗(100*3)，得到14.9g油状物，纯度99％，收率95％。
1H-NMR(300MHz,d6-MDSO):δ8.00(d,2H)；7.66(t,1H)；7.51(t,2H)；7.11(s,1H)；7.05(s,1H)；4.39(t,2H)；4.01(s,2H)；3.70(t,2H)；3.59(d,2H)；2.95-2.84(m,3H)；2.08(t,2H)；1.11(d,3H).EIMS m/z 364.2([M+H]+)
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.一种具有式Ⅰ结构中间体的制备方法：
其特征在于，该制备方法为在叔丁醇钾条件、三环己基膦及双-(1,5-环辛二烯)镍催化下，将式Ⅱ与式Ⅲ进行偶联反应制备式Ⅳ，式Ⅳ脱去保护基Boc制备化合物Ⅰ；
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