CN114539318B - 开环葫芦脲磷酸盐化合物及其制备和在药物增溶中的应用 - Google Patents
开环葫芦脲磷酸盐化合物及其制备和在药物增溶中的应用 Download PDFInfo
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- CN114539318B CN114539318B CN202210249153.4A CN202210249153A CN114539318B CN 114539318 B CN114539318 B CN 114539318B CN 202210249153 A CN202210249153 A CN 202210249153A CN 114539318 B CN114539318 B CN 114539318B
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- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 27
- -1 cucurbituril phosphate compound Chemical class 0.000 title claims abstract description 27
- 239000010452 phosphate Substances 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 230000007928 solubilization Effects 0.000 title claims abstract description 9
- 238000005063 solubilization Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 14
- 238000006467 substitution reaction Methods 0.000 claims abstract description 8
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical group CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000004202 carbamide Chemical group 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- 239000002244 precipitate Substances 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 11
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 8
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 7
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- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims 1
- 229960001596 famotidine Drugs 0.000 claims 1
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- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims 1
- MSBXTPRURXJCPF-DQWIULQBSA-N cucurbit[6]uril Chemical class N1([C@@H]2[C@@H]3N(C1=O)CN1[C@@H]4[C@@H]5N(C1=O)CN1[C@@H]6[C@@H]7N(C1=O)CN1[C@@H]8[C@@H]9N(C1=O)CN([C@H]1N(C%10=O)CN9C(=O)N8CN7C(=O)N6CN5C(=O)N4CN3C(=O)N2C2)C3=O)CN4C(=O)N5[C@@H]6[C@H]4N2C(=O)N6CN%10[C@H]1N3C5 MSBXTPRURXJCPF-DQWIULQBSA-N 0.000 abstract description 8
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明公开了一种开环葫芦脲磷酸盐化合物及其制备和在药物增溶中的应用,所述开环葫芦脲磷酸盐化合物为一种磷酸官能团化的开环葫芦脲化合物,由羟基取代的苯环、亚磷酸三乙酯和脲四聚体为主要原料,通过一系列取代、缩合反应得到。相较于现有技术中已有的磺酸基、胺基、羧基取代的开环葫芦脲化合物,其表现出更优良的溶解性和增溶能力,在药物制剂领域有极大的应用潜力。
Description
技术领域
本发明属于开环葫芦脲化合物,具体涉及一种磷酸官能团化开环葫芦脲结构,更具体的,涉及一种开环葫芦脲磷酸盐化合物及其制备方法,以及其作为增溶剂在药物制剂领域的应用。
背景技术
制剂中的活性药物成分(API)按照生物药剂学分类系统可以分为四类:①高溶解性高渗透性药物,②低溶解性高渗透性药物,③高溶解性低渗透性药物,④低溶解性低渗透性药物。根据文献报道,目前在研的40~70%新化学实体都属于第②类药物。为了解决药物的溶解性问题,制剂工业发展了诸多技术,例如成盐、共晶、前药等。其中,超分子主体通过非共价键作用包裹药物分子形成的包合物,不仅能够改善药物的水溶性,还能够提高药物的稳定性、生物利用率等性质,故而能作为增溶剂用于药物制剂的配方中。目前,已有不少超分子主体被收录于药典作为药用辅料使用,例如羟丙基-β-环糊精(HP-β-CD)、磺丁基-β-环糊精(SBE-β-CD)等。
开环葫芦脲是一类新型的超分子主体,由Isaacs小组于2010年率先合成并报道,该类羧基官能团化开环葫芦脲结构得到了单晶X射线衍射的确认(J.Org.Chem.2010,75,4786-4795)。该类开环葫芦脲的结构特征是:一个中间的C型甘脲四聚体分子骨架,两个末端取代的芳香环,四个羧酸阴离子取代的烷基侧链。相较于传统的葫芦脲,开环葫芦脲的稠合多环骨架能够像手一样弯曲,包裹不同尺寸的药物分子。其后,该小组又陆续报道了磺酸基(Nat.Chem.2012,4,503-510)、胺基(Org.Biomol.Chem.2014,12,2413-2422)取代的开环葫芦脲化合物。不同取代基团、烷基侧链和芳香环的开环葫芦脲的溶解性有显著差异,还会影响其对各种药物的包合能力和增溶能力。
现有的开环葫芦脲具有如下所示的结构通式I:
其中,芳香环Ar为苯环或萘环,侧链长度n为1~3,取代基团R为-COO-、-SO3 -、-NH3 +等。但是目前已知的开环葫芦脲的溶解性有限,限制了其应用。
发明内容
有鉴于此,本发明的目的在于在上述通式I的基础上,改变化合物结构,得到具有更优良的溶解性和增溶能力的类似物。
为了实现上述目的,本发明的技术方案具体如下:
本发明提供了一种开环葫芦脲磷酸盐化合物,其结构如通式II所示:
其中,M为金属元素,n为1、2或3。
优选地,所述M为K、Na或Li。
本发明还提供了制备上述开环葫芦脲磷酸盐化合物的方法,包括以下步骤:
S1、化合物A与四溴化碳、三苯基膦发生取代反应得到化合物B;
S2、化合物B与亚磷酸三乙酯发生取代反应得到化合物C;
S3、化合物C与脲四聚体进行缩合反应,淬灭纯化后得到磷酸酯官能团化开环葫芦脲化合物;
S4、磷酸酯官能团化开环葫芦脲化合物与三甲基溴硅烷反应脱去酯基后,再与无机碱的水溶液反应,即得开环葫芦脲磷酸盐化合物;
所述化合物A、B、C的结构式分别为:
式中,n为1~3。
优选地,步骤S2所述取代反应的条件为:以二甲苯为溶剂,化合物B与亚磷酸三乙酯的摩尔比为1∶5~50,反应温度为120~160℃,反应时间为24~96h。
优选地,步骤S3所述缩合反应的条件为:以三氟醋酸和醋酸酐的混合液为溶剂,化合物C与脲四聚体的摩尔比为1∶0.1~0.5,反应温度为50~80℃,反应时间为4~10h。更加优选地,所述三氟醋酸和所述醋酸酐的体积比为3∶1~1∶3。
优选地,步骤S3所述淬灭纯化具体为:待缩合反应结束后,将反应液倒入甲醇中淬灭,减压蒸馏除去过量溶剂,再加入乙醚得到沉淀,过滤干燥即为磷酸酯官能团化开环葫芦脲化合物,其结构通式如图1所示。
优选地,步骤S4所述脱去酯基的反应的条件为:以二氯甲烷为溶剂,磷酸酯官能团化开环葫芦脲化合物与三甲基溴硅烷的摩尔比为1∶10~50,反应温度为0~30℃,反应时间为24~96h。
优选地,步骤S4所述无机碱为氢氧化锂、氢氧化钠或氢氧化钾且其反应温度为0~30℃。
本发明还提供了上述开环葫芦脲磷酸盐化合物作为增溶剂在药物制剂领域中的应用,其能显著提高药物的水溶性。
本发明的有益效果为:本发明制备得到了一种磷酸官能团化开环葫芦脲,相较于现有已知结构的开环葫芦脲,其在药物制剂领域表现出更优良的溶解性和增溶能力,而且制备产率较高,适于工业化应用。
附图说明
图1为本发明制备的磷酸酯官能团化开环葫芦脲化合物的结构示意图;
图2为实施例1中开环葫芦脲磷酸盐化合物的制备工艺流程图;
图3为实施例2中各中间产物和终产物的结构示意图;
图4为实施例3中各中间产物和终产物的结构示意图。
具体实施方式
下面将结合本发明中的实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
实施例1
参考图2,开环葫芦脲磷酸盐化合物的制备步骤如下:
(1)将1,4-双(2-羟乙氧基)苯(8.45g,42.63mmol)、三苯基膦(26.62g,101.49mmol)和无水乙腈(160ml)加入到500ml三颈烧瓶中,在0℃下剧烈搅拌。将四溴化碳(33.63g,101.41mmol)和50ml无水乙腈配置成溶液,通过滴液漏斗缓慢加入反应体系中。滴加完毕后,将反应体系升至室温,搅拌约4小时,TLC跟踪原料基本反应完全。向反应体系中加入水,生成白色沉淀,过滤收集沉淀,用甲醇和水的混合溶液洗涤。将沉淀转移至烧瓶中,加入甲醇进行重结晶,过滤干燥后,得到白色固体化合物1(12.63g,产率91.43%)。其中,化合物1的测定:1H NMR(400MHz,DMSO-d6):δ6.90(s,4H),4.25(t,4H),3.77(t,4H)。
(2)将化合物1(6.55g,20.22mmol)、亚磷酸三乙酯(33.59g,202.16mmol)和二甲苯(66ml)加入250ml烧瓶中,搅拌,加热至140℃。反应约72小时,TLC跟踪至产物点相对最浓时,反应结束。减压蒸馏除去过量的原料和溶剂,粗产品用柱层析纯化,得到淡黄色液体化合物2(8.69g,产率98.07%)。化合物2的测定结果为:1H NMR(400MHz,CDCl3):δ6.83(s,4H),4.16(t,4H),4.13(m,8H),2.28(dt,4H),1.34(t,12H);13C NMR(400MHz,CDCl3):δ152.5,115.4,62.5,61.5,27.1,25.7,16.2。
(3)将化合物2(4.64g,10.5mmol)和化合物3(2.07g,2.65mmol)加入50ml烧瓶中,再加入14ml三氟乙酸和14ml醋酸酐混合溶液,在70℃搅拌反应6小时。反应结束后,将反应体系倒入甲醇中淬灭,减压蒸馏除去过量溶剂,得到褐色油状粘稠液体。冷却后,向浓缩液中加入乙醚,出现白色沉淀,过滤干燥,得到淡黄色固体化合物4(3.90g,产率90.71%)。化合物4具有高吸水性,储存于高真空环境中。
(4)将化合物4(1.36g,0.84mmol)和无水二氯甲烷(15ml)加入50ml三颈烧瓶中剧烈搅拌,氮气保护。将三甲基溴硅烷(2.57g,16.8mmol)和无水二氯甲烷(9ml)配置溶液,通过滴液漏斗缓慢加入反应体系中。滴加完毕后,将反应体系升至室温,反应72小时。反应结束后,将反应体系倒入碎冰中,析出白色沉淀。过滤收集沉淀,依次用少量甲醇、二氯甲烷、乙醚洗涤,干燥,得到白色固体化合物5(0.59g,产率42.67%)。
向化合物5(0.59g,0.42mmol)中加入1N的氢氧化钠溶液3ml,完全溶解。减压蒸馏除去溶剂,得到淡黄色固体,即化合物5的钠盐。其检测结果如下:1H NMR(400MHz,D2O):δ7.17(s,4H),5.74(d,2H),5.59(d,4H),5.48(q,4H),5.21(d,4H),4.43(d,4H),4.28(m,8H),4.18(m,4H),4.14(d,2H),1.96(m,8H),1.82(s,6H),1.71(s,6H);13C NMR(400MHz,D2O):δ157.1,156.5,150.5,129.0,118.4,78.8,77.7,71.5,70.2,53.1,48.6,35.6,30.4,29.6,16.2,14.9;MS(ESI):m/z 1395.3([M-H]-),1417.3([M-2H+Na]-);HRMS(MALDI):calcd forC50H62O24N16P4697.1542,found 697.1545。
实施例2
(1)将1,4-双(2-羟丙氧基)苯(9.81g,43.36mmol)、三苯基膦(27.29g,104.06mmol)和无水乙腈(170ml)加入到500ml三颈烧瓶中,在0℃下剧烈搅拌。将四溴化碳(34.51g,104.06mmol)和50ml无水乙腈配置溶液,通过滴液漏斗缓慢加入反应体系中。滴加完毕后,将反应体系升至室温,搅拌约4小时,TLC跟踪原料基本反应完全。向反应体系中加入水,生成白色沉淀,过滤收集沉淀,用甲醇和水的混合溶液洗涤。将沉淀转移至烧瓶中,加入甲醇进行重结晶,过滤干燥后,得到白色固体化合物6(13.69g,产率89.71%)。化合物6的检测结果为:1H NMR(400MHz,DMSO-d6):δ6.90(s,4H),4.02(t,4H),3.45(t,4H),2.07(m,4H)。
(2)将化合物6(6.89g,19.58mmol)、亚磷酸三乙酯(32.53g,195.80mmol)和二甲苯(60ml)加入250ml烧瓶中,搅拌,加热至140℃。反应约72小时,TLC跟踪至产物点相对最浓时,反应结束。减压蒸馏除去过量的原料和溶剂,粗产品用柱层析纯化,得到淡黄色液体化合物7(8.34g,产率91.27%)。化合物7的检测结果为:1H NMR(400MHz,CDCl3):δ6.83(s,4H),4.13(m,8H),3.98(t,4H),1.87(m,4H),1.66(m,4H),1.34(t,12H);13C NMR(400MHz,CDCl3):δ152.5,115.4,62.5,61.5,28.2,27.1,16.2,15.0。
(3)将化合物7(5.49g,12.52mmol)和化合物3(2.44g,3.13mmol)加入50ml烧瓶中,再加入18ml三氟乙酸和18ml醋酸酐混合溶液,在70℃搅拌反应6小时。反应结束后,将反应体系倒入甲醇中淬灭,减压蒸馏除去过量溶剂,得到褐色油状粘稠液体。冷却后,向浓缩液中加入乙醚,出现白色沉淀,过滤干燥,得到淡黄色固体化合物8(5.10g,产率97.06%)。化合物8具有高吸水性,储存于高真空环境中。
(4)将化合物8(2.28g,1.36mmol)和无水二氯甲烷(25ml)加入100ml三颈烧瓶中剧烈搅拌,氮气保护。将三甲基溴硅烷(4.16g,27.20mmol)和无水二氯甲烷(15ml)配置溶液,通过滴液漏斗缓慢加入反应体系中。滴加完毕后,将反应体系升至室温,反应72小时。反应结束后,将反应体系倒入碎冰中,析出白色沉淀。过滤收集沉淀,依次用少量甲醇、二氯甲烷、乙醚洗涤,干燥,得到白色固体化合物9(0.77g,产率39.12%)。
向化合物9(0.77g,0.50mmol)中加入1N的氢氧化钾溶液4ml,完全溶解。减压蒸馏除去溶剂,得到淡黄色固体,即化合物9的钾盐。化合物9的检测数据为:1H NMR(400MHz,D2O):δ7.17(s,4H),5.74(d,2H),5.59(d,4H),5.48(q,4H),5.21(d,4H),4.43(d,4H),4.28(m,8H),4.18(m,4H),4.14(d,2H),2.33(m,8H),1.96(m,8H),1.82(s,6H),1.71(s,6H);13CNMR(400MHz,D2O):δ157.1,156.5,150.5,129.0,118.4,78.8,77.7,71.5,70.2,53.1,48.6,40.7,35.6,30.4,29.6,16.2,14.9;MS(ESI):m/z 1450.2([M-H]-),1488.2([M-2H+K]-);HRMS(MALDI):calcd for C54H70O24N16P4 724.6231,found 724.6232。
实施例3
将1,4-双(2-羟丁氧基)苯(10.32g,40.57mmol)、三苯基膦(25.54g,97.37mmol)和无水乙腈(150ml)加入到500ml三颈烧瓶中,在0℃下剧烈搅拌。将四溴化碳(32.29g,97.37mmol)和50ml无水乙腈配置溶液,通过滴液漏斗缓慢加入反应体系中。滴加完毕后,将反应体系升至室温,搅拌约4小时,TLC跟踪原料基本反应完全。向反应体系中加入水,生成白色沉淀,过滤收集沉淀,用甲醇和水的混合溶液洗涤。将沉淀转移至烧瓶中,加入甲醇进行重结晶,过滤干燥后,得到白色固体化合物10(14.41g,产率93.46%)。化合物10的检测结果为:1H NMR(400MHz,DMSO-d6):δ6.90(s,4H),4.01(t,4H),3.48(t,4H),1.77(m,4H),1.75(m,4H)。
(2)将化合物10(5.79g,15.23mmol)、亚磷酸三乙酯(25.31g,152.32mmol)和二甲苯(50ml)加入250ml烧瓶中,搅拌,加热至140℃。反应约72小时,TLC跟踪至产物点相对最浓时,反应结束。减压蒸馏除去过量的原料和溶剂,粗产品用柱层析纯化,得到淡黄色液体化合物11(7.20g,产率95.61%)。化合物11的检测结果为:1H NMR(400MHz,CDCl3):δ6.83(s,4H),4.13(m,8H),3.96(t,4H),1.68(m,4H),1.65(m,4H),1.34(t,12H),1.18(m,4H);13C NMR(400MHz,CDCl3):δ152.5,115.4,62.5,61.5,30.3,27.1,25.7,16.2,11.4。
(3)将化合物11(3.37g,7.69mmol)和化合物3(1.50g,1.92mmol)加入50ml烧瓶中,再加入10ml三氟乙酸和10ml醋酸酐混合溶液,在70℃搅拌反应6小时。反应结束后,将反应体系倒入甲醇中淬灭,减压蒸馏除去过量溶剂,得到褐色油状粘稠液体。冷却后,向浓缩液中加入乙醚,出现白色沉淀,过滤干燥,得到淡黄色固体化合物12(3.09g,产率92.85%)。化合物12具有高吸水性,储存于高真空环境中。
(4)将化合物12(1.82g,1.05mmol)和无水二氯甲烷(20ml)加入50ml三颈烧瓶中剧烈搅拌,氮气保护。将三甲基溴硅烷(3.22g,21.0mmol)和无水二氯甲烷(12ml)配置溶液,通过滴液漏斗缓慢加入反应体系中。滴加完毕后,将反应体系升至室温,反应72小时。反应结束后,将反应体系倒入碎冰中,析出白色沉淀。过滤收集沉淀,依次用少量甲醇、二氯甲烷、乙醚洗涤,干燥,得到白色固体化合物13(0.57g,产率35.73%)。
向化合物13(0.57g,0.38mmol)中加入1N的氢氧化锂溶液3ml,完全溶解。减压蒸馏除去溶剂,得到淡黄色固体,即化合物13的锂盐。其检测结果为:1H NMR(400MHz,D2O):δ7.17(s,4H),5.74(d,2H),5.59(d,4H),5.48(q,4H),5.21(d,4H),4.43(d,4H),4.28(m,8H),4.18(m,4H),4.14(d,2H),2.37(m,8H),2.14(m,8H),1.96(m,8H),1.82(s,6H),1.71(s,6H);13CNMR(400MHz,D2O):δ157.1,156.5,150.5,129.0,118.4,78.8,77.7,71.5,70.2,53.1,48.6,41.5,35.6,30.4,29.6,16.2,14.9,11.8;MS(ESI):m/z 1508.1([M-H]-),1530.1([M-2H+Na]-);HRMS(MALDI):calcd for C58H78O24N16P4 753.4928,found 753.4936。
实施例4
对实施例1~3制备的终产物的增溶能力进行检测,具体过程如下:
将过量药物加入到装有1mLPBS溶液(pH值=7.4)和不同浓度的磷酸官能团化开环葫芦脲(分别为0mM,30mM,60mM,90mM,120mM,150mM)的玻璃小瓶中,将小瓶在水平旋转振荡器上以50rpm的速度在25℃下振荡24小时,然后将溶液通过0.45mm尼龙圆盘过滤器,收集澄清溶液,最后通过UV-Vis光谱仪测定溶液中药物的溶解度。结果如下表所示:
现有的磺酸官能团化的开环葫芦脲能分别将喜树碱和利福平的水溶性提高至11.8mM和46mM。相较而言,本发明提供的开环葫芦脲对一些药物的增溶能力得到了显著提升。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。
Claims (7)
1.一种开环葫芦脲磷酸盐化合物在药物增溶中的应用,其特征在于,所述开环葫芦脲磷酸盐化合物的结构通式如下所示:
其中,M为K、Na或Li,n为1~3;
所述开环葫芦脲磷酸盐化合物的制备方法包括以下步骤:
S1、化合物A与四溴化碳、三苯基膦发生取代反应得到化合物B;
S2、化合物B与亚磷酸三乙酯发生取代反应得到化合物C;
S3、化合物C与脲四聚体进行缩合反应,淬灭纯化后得到磷酸酯官能团化开环葫芦脲化合物;
S4、磷酸酯官能团化开环葫芦脲化合物与三甲基溴硅烷反应脱去酯基后,再与无机碱的水溶液反应,即得开环葫芦脲磷酸盐化合物;
所述化合物A、B、C的结构式分别为:
式中,n为1~3;
所述药物为喜树碱、法莫替丁或利福平。
2.根据权利要求1所述的应用,其特征在于,步骤S2所述取代反应的条件为:以二甲苯为溶剂,化合物B与亚磷酸三乙酯的摩尔比为1∶5~50,反应温度为120~160℃,反应时间为24~96h。
3.根据权利要求1所述的应用,其特征在于,步骤S3所述缩合反应的条件为:以三氟醋酸和醋酸酐的混合液为溶剂,化合物C与脲四聚体的摩尔比为1∶0.1~0.5,反应温度为50~80℃,反应时间为4~10h。
4.根据权利要求3所述的应用,其特征在于,所述三氟醋酸和所述醋酸酐的体积比为3∶1~1∶3。
5.根据权利要求1所述的应用,其特征在于,步骤S3所述淬灭纯化具体为:待缩合反应结束后,将反应液倒入甲醇中淬灭,减压蒸馏除去过量溶剂,再加入乙醚得到沉淀,过滤干燥即为磷酸酯官能团化开环葫芦脲化合物。
6.根据权利要求1所述的应用,其特征在于,步骤S4所述脱去酯基的反应的条件为:以二氯甲烷为溶剂,磷酸酯官能团化开环葫芦脲化合物与三甲基溴硅烷的摩尔比为1∶10~50,反应温度为0~30℃,反应时间为24~96h。
7.根据权利要求1所述的应用,其特征在于,步骤S4所述无机碱为氢氧化锂、氢氧化钠或氢氧化钾且其反应温度为0~30℃。
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