CN101143880A - 膦异香豆素盐及其制备方法 - Google Patents
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- -1 Phosphine isocoumarin salt Chemical class 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims description 51
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims description 41
- IQZZFVDIZRWADY-UHFFFAOYSA-N isocumarine Natural products C1=CC=C2C(=O)OC=CC2=C1 IQZZFVDIZRWADY-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 125000003118 aryl group Chemical group 0.000 claims abstract description 14
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 229910052792 caesium Inorganic materials 0.000 claims abstract description 4
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 4
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 4
- 229910052701 rubidium Inorganic materials 0.000 claims abstract description 4
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 4
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- FGDZQCVHDSGLHJ-UHFFFAOYSA-M rubidium chloride Chemical compound [Cl-].[Rb+] FGDZQCVHDSGLHJ-UHFFFAOYSA-M 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Inorganic materials [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 229910004013 NO 2 Inorganic materials 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Inorganic materials [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 5
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 16
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000002532 enzyme inhibitor Substances 0.000 abstract description 2
- 150000002512 isocoumarins Chemical class 0.000 abstract 3
- 239000002585 base Substances 0.000 abstract 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 abstract 1
- 239000011734 sodium Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 230000006837 decompression Effects 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 208000010749 gastric carcinoma Diseases 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940058344 antitrematodals organophosphorous compound Drugs 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 239000003063 flame retardant Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002903 organophosphorus compounds Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
本发明涉及一种新型膦异香豆素盐及其制备方法。本发明的化合物具有如右分子式,其中,R=H,C1-10的烷基,C3-7的环烷基,芳基,及它们的取代衍生物;Z=Li,Na,K,Rb,Cs;Y=H,C1-4的烷基,烷氧基,羰基、卤素,CN,CF3,NO2,OH,胺基,芳基;X=H,Cl,Br,I,C1-10的烷基,C3-7的环烷基,芳基,及它们的取代衍生物。所述膦异香豆素盐是由膦异香豆素酯在碱金属盐的作用下发生反应制备的。本发明所述膦异香豆素盐具有一定的水溶性,在酶抑制剂和抗肿瘤等相关领域具有良好的应用前景。
Description
技术领域
本发明涉及一种含磷杂环化合物,特别是涉及膦异香豆素盐(苯并烯醇膦酸内酯)及其制备方法。
背景技术
有机磷化合物不仅在生命体系中担当非常重要的角色,而且有广泛的商业用途,如作为杀虫剂、除草剂、阻燃剂和润滑剂,其中,许多具有重要生物活性的有机磷杂环化合物不断被发现和合成出来(Engel,R.,Ed.Handbook ofOrgnophosphorus Chemistry;MarcelDekker:New York,1992;Chapter11;Quin,L.D.,Ed.AGuide toOrganophosphorus Chemistry;John Wiley&Sons:New York,2000;Chapter11)。在发明人以前的工作中,首次合成了一类具有潜在生物活性的新型磷杂环化合物,即膦异香豆素酯A(专利号ZL03151003.5),通过初步的生物活性测试表明,这类化合物对蛋白酪氨酸磷酸酯酶PTP1B有中等的抑制活性,对人胃癌细胞BGC和人肝癌细胞HepG2有中等的细胞毒性(Peng,A.-Y.;Ding,Y.-X.J.Am.Chem.Soc.2003,125,15006-15007;Peng,A.-Y.;Ding,Y.-X.Org.Lett.2004,6,1119-1121;Peng,A.-Y.;Ding,Y.-X.Tetrahedron,2005,61,10303-10308)。但是,膦异香豆素酯A很差的水溶性大大限制了这类化合物的实际应用。
发明内容
本发明要解决的问题是提供一类具有一定水溶性的新型磷杂环化合物,即膦膦异香豆素盐。
本发明要解决的另一问题是提供一种所述膦异香豆素盐的制备方法。
本发明提供的膦异香豆素盐具有如下分子式B:
其中,R=H,C1-10的烷基,C3-7的环烷基,芳基,及它们的取代衍生物;Z=Li,Na,K,Rb,Cs;R1=C1-5的烷基;Y=H,C1-4的烷基,CH3O,卤素,CN,CF3,NO2,OH,胺基,羰基、芳基;X=H,Cl,Br,I,C1-10的烷基,C3-7的环烷基,芳基,及它们的取代衍生物,所述的烷基、环烷基、芳基的取代衍生物的取代基优选为C1-5的烷基、羰基、烷基、C1-5的烷氧基、卤素、NO2、氨或胺基。
所述的芳基包括碳芳环和杂芳环,优选为苯基、萘基、吡咯基、呋喃基、噻吩基、吡啶基等。上述的烷基均可以含有不饱和键。所述的羰基例如为羧基、烷氧羰基、酮基,后二者的烷基部分和R代表的范围相同,例如R=H,C1-10的烷基,C3-7的环烷基,芳基。
膦异香豆素酯水解磷的环外酯基可以在碱金属盐的作用下发生反应完成,该反应具有高度的化学选择性,只断开环外的烷氧键,而磷杂环仍然保持完整。
A可以与多种碱金属盐发生此反应,得到膦异香豆素盐B(Z=Li,Na,K,Rb,Cs)。膦异香豆素锂盐可以用LiCl,LiBr,或LiI制备,膦异香豆素钠盐可以用如NaCl,NaBr,或NaI制备,膦异香豆素钾盐可以用KCl,KBr,或KI制备,膦异香豆素铷盐可以用RbCl制备,膦异香豆素铯盐可以用CsF,或CsCl制备。
所述的反应在有机溶剂中进行,所述的有机溶剂,包括甲苯、1,4-二氧六环、乙腈、氯仿、二氯甲烷、THF(四氢呋喃)、乙酸乙酯、DMF(N,N-二甲基甲酰胺)、HMPA(六甲基磷酸三胺)或DMSO(二甲基亚砜)均可应用。
上述反应中,用碱金属盐制备时,膦异香豆素酯、碱金属盐的反应摩尔比推荐为1∶1.2~4,反应推荐在回流温度反应2~24小时。
上面所涉及到的膦异香豆素酯大都难溶于水,通过上述反应得到的膦异香豆素盐,与相应的膦异香豆素酯相比,其水溶性得到明显改善,它们在水中的溶解度在0.05g/1g水到0.4g/1g水之间。
初步的生物活性测试表明,膦异香豆素酯对蛋白酪氨酸磷酸酯酶PTP1B有中等的抑制活性,对人胃癌细胞BGC和人肝癌细胞HepG2有中等的细胞毒性。具有良好水溶性的膦异香豆素盐在酶抑制剂和抗肿瘤等相关领域具有更好的应用前景。
总体而言,本发明所述的膦异香豆素盐,与膦异香豆素酯相比,其水溶性得到明显改善,它们在医药、农药和相关领域具有更良好的应用前景。其制备方法简便、高效。
具体实施方式
通过下述实施例将有助于进一步理解本发明,但不用于限制本发明的内容。
实施例一:
制备膦异香豆素碱金属盐的典型操作:在氮气保护下,25ml蛋形瓶内加入50mg(0.175mmol)3-苯基膦异香豆素乙酯,9mg(0.210mmol)LiCl和1ml无水丙酮,回流(油浴温度约60℃)搅拌12小时,TLC检测已反应完全,减压去除丙酮溶剂,得到的白色固体用冰的丙酮洗涤,干燥后即得白色固体37mg,产率为80%。它在水中的溶解度约为0.080g/1g水。1H NMR:δ7.74-7.83(m,3H),7.22-7.34(m,6H),6.82(s,1H);ESI-MS:287(M+Na,100)。
实施例二:
制备膦异香豆素钠盐的典型操作:其中所用膦异香豆素酯是7-氯-3-苯基膦异香豆素乙酯,反应物的摩尔用量与实施例一相同,实验操作基本同实施例一,不同的是使用的碱金属盐是NaI,反应溶剂为无水DMF,反应温度为80℃,反应15小时,反应完后加甲苯共沸减压除去DMF溶剂。该产物为白色固体,产率为82%。它在水中的溶解度约为0.085g/1g水。1H NMR:δ7.74-7.80(m,2H),7.66-7.75(m,1H),7.29-7.38(m,4H),6.75(s,1H);ESI-MS:337(M+Na,100)。
实施例三:
制备膦异香豆素钾盐的典型操作:其中所用膦异香豆素酯是7-甲氧基-4-溴-3-苯基膦异香豆素乙酯,反应物的摩尔用量与实施例一相同,实验操作基本同实施例二,不同的是使用的碱金属盐是KI,反应溶剂为无水1,4-二氧六环,反应温度为80℃,反应12小时,反应完后减压除去1,4-二氧六环溶剂。该产物为白色固体,产率为75%。它在水中的溶解度约为0.075g/1g水。1H NMR:δ7.81-7.86(m,1H),7.61-7.65(m,2H),7.38-7.42(m,3H),7.21-7.32(m,2H),3.85(s,3H);ESI-MS:427(M+Na,100)。
实施例四:
制备膦异香豆素铷盐的典型操作:其中所用膦异香豆素酯是7-氯-3-环丙基膦异香豆素乙酯,反应物的摩尔用量与实施例二相同,实验操作基本同实施例二,不同的是使用的碱金属盐是RbCl,反应溶剂为无水甲苯,反应温度为100℃,反应20小时,反应完后减压除去甲苯溶剂。该产物为白色固体,产率为65%。它在水中的溶解度约为0.092g/1g水。1H NMR:δ7.70-7.76(m,1H),7.40-7.45(m,1H),7.05-7.10(m,1H),5.91(d,J=0.9Hz,1H),1.60-1.70(m,1H),0.81-0.90(m,4H);ESI-MS:m/z:363(M+Na,100).。
实施例五:
制备膦异香豆素铷盐的典型操作:其中所用膦异香豆素酯是4-苯乙炔基-3-苯基膦异香豆素乙酯,反应物的摩尔用量与实施例二相同,实验操作基本同实施例二,不同的是使用的碱金属盐是CsCI,该产物为白色固体,产率为61%。它在水中的溶解度约为0.095g/1g水。1H NMR:δ7.29-8.06(m,14H);ESI-MS:m/z:381(M+Na,100)。
Claims (8)
1.一种膦异香豆素盐,其特征是,具有如下分子式:
其中,R=H,C1-10的烷基,C3-7的环烷基,芳基,及它们的取代衍生物;Z=Li,Na,K,Rb,Cs;Y=H,C1-4的烷基,烷氧基,羰基、卤素,CN,CF3,NO2,OH,胺基,芳基;X=H,Cl,Br,I,C1-10的烷基,C3-7的环烷基,芳基,及它们的取代衍生物;所述的烷基、环烷基、芳基的取代衍生物的取代基为C1-5的烷基、羰基、羟基、C1-5的烷氧基、卤素、NO2、氨或胺基。
2.根据权利要求1所述膦异香豆素盐,其特征是,所述的芳基是苯基、萘基、吡咯基、呋喃基、噻吩基或吡啶基。
3.根据权利要求1所述膦异香豆素盐,其特征是,所述的羰基为羧基、烷氧羰基或酮基。
5.根据权利要求4所述膦异香豆素盐的制备方法,其特征是,所述的碱金属盐是Li(I)盐,Na(I)盐,K(I)盐,Rb(I)盐或Cs(I)盐。
6.根据权利要求4所述膦异香豆素盐的制备方法,其特征是,所述的Li(I)为LiCl,LiBr或LiI;Na(I)为NaCl,NaBr,或NaI;K(I)为KCl,KBr,或KI;Rb(I)为RbCl或Cs(I)为CsF或CsCl。
7.根据权利要求4所述膦异香豆素盐的制备方法,其特征是,所述的反应在有机溶剂中进行,该有机溶剂为丙酮、甲苯、1,4-二氧六环、 乙腈、 氯仿、二氯甲烷、THF、DMF、HMPA或DMSO。
8.根据权利要求4所述膦异香豆素盐的制备方法,其特征是,在所述的反应中,膦异香豆素酯与碱金属盐的反应摩尔比为1∶1.2~4,在回流温度反应2~24小时。
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CN101367840B (zh) * | 2008-10-06 | 2011-06-01 | 中山大学 | 膦异香豆素酰胺及其合成方法与应用 |
JPWO2016024605A1 (ja) * | 2014-08-12 | 2017-05-25 | 大塚化学株式会社 | 環状ホスホン酸ナトリウム塩の結晶及びその製造方法 |
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CN101367840B (zh) * | 2008-10-06 | 2011-06-01 | 中山大学 | 膦异香豆素酰胺及其合成方法与应用 |
JPWO2016024605A1 (ja) * | 2014-08-12 | 2017-05-25 | 大塚化学株式会社 | 環状ホスホン酸ナトリウム塩の結晶及びその製造方法 |
US10385081B2 (en) | 2014-08-12 | 2019-08-20 | Otsuka Chemical Co., Ltd. | Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same |
JP2020109131A (ja) * | 2014-08-12 | 2020-07-16 | 大塚化学株式会社 | 環状ホスホン酸ナトリウム塩の結晶及びその製造方法 |
US10774100B2 (en) | 2014-08-12 | 2020-09-15 | Otsuka Checmial Co., Ltd. | Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same |
US10941169B2 (en) | 2014-08-12 | 2021-03-09 | Otsuka Chemical Co., Ltd. | Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same |
US11168101B2 (en) | 2014-08-12 | 2021-11-09 | Otsuka Chemical Co., Ltd. | Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same |
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