CN111072734A - 一种尿嘧啶核苷衍生物及该衍生物制备去氧氟尿苷药物的方法 - Google Patents
一种尿嘧啶核苷衍生物及该衍生物制备去氧氟尿苷药物的方法 Download PDFInfo
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- CN111072734A CN111072734A CN201911268130.2A CN201911268130A CN111072734A CN 111072734 A CN111072734 A CN 111072734A CN 201911268130 A CN201911268130 A CN 201911268130A CN 111072734 A CN111072734 A CN 111072734A
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- 238000000034 method Methods 0.000 title claims abstract description 19
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- 229940113082 thymine Drugs 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
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Abstract
本发明公开了一种如通式(I)所示的5‑脱氧‑D‑呋喃核糖1‑[2‑(1‑苯乙烯基)苯甲酸酯]衍生物以及该衍生物的制备方法,其中通式(I)的结构为
Description
技术领域
本发明涉及药物化学技术领域,更具体的说是涉及一种利用5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物制备去氧氟尿苷药物和该衍生物的合成方法。
背景技术
5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物是作为合成核糖类药物的重要原料,可以与嘧啶或嘌呤类化合物直接进行糖苷化反应,生成具有重要生理活性的核苷类分子。
去氧氟尿苷(Doxifluridine),为氟尿嘧啶(5-Fluorouracil,5-FU)的前体药物。在肿瘤组织内经过胸腺嘧啶核苷磷酸化酶作转化为氟尿嘧啶,从而抑制肿瘤细胞DNA、RNA的生物合成,发挥其抗肿瘤的作用。所以其抗肿瘤的专一性较强,毒性较低,临床常用于胃癌、结肠直肠癌、乳腺癌。
目前相关专利报道的去氧氟尿苷的合成路线主要分为两类,现列举如下:
第一类(Scheme 1-3):以制备所得的三乙酰去氧核糖为原料,在当量的路易斯酸下(三氟甲磺酸三甲基硅酯或四氯化锡)与2,4-二-O-(三甲基硅基)-5-氟尿嘧啶反应制备核苷,然后在碱性条件下脱去乙酰基保护基。但是其中的核苷化反应条件较为剧烈,对很多官能团不兼容。
Scheme 1:
Scheme 2:
Scheme 3:
第二类(Scheme 4-6):以核糖为原料制备得到5-氟尿嘧啶核苷,再进行官能团转化得到去氧核苷。但是其中的官能团转化路线较长,通常所得副产物较多,反应条件对于很多官能团不兼容。
Scheme 4:
Scheme 5:
Scheme 6:
因此,如何提供一种原料以实现在温和条件下高选择性、高效率的制备去氧氟尿苷是本领域技术人员亟需解决的问题。
发明内容
有鉴于此,本发明提供了一种5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物,以及采用该衍生物与尿嘧啶衍生物为原料,在温和条件下高选择性、高收率制备去氧氟尿苷的方法。
为了达到上述目的,本发明采用如下技术方案:
一种5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物,所述衍生物的结构如通式(I)所示:
通式(I)中R1为酰基,包括但不限于苯甲酰基、乙酰基、乙酰丙酰基、特戊酰基。
本发明还提供了一种上述5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物的制备方法,包括以下步骤:
(1)将通式(Ⅱ)表示的化合物在路易斯酸条件下与对甲苯硫酚发生糖苷化反应,得到通式(Ⅲ);
(2)将通式(Ⅲ)表示的化合物在三氯异氰尿酸条件下脱硫苷得到通式(Ⅳ);
(3)将通式(Ⅳ)表示的化合物与2-(1-苯乙烯基)苯甲酸进行缩合反应得到通式(I);
通式(Ⅱ)、通式(Ⅲ)、通式(Ⅳ)表示的化合物的结构分别如下:
其中,R1为酰基,包括但不限于苯甲酰基、乙酰基、乙酰丙酰基、特戊酰基。
优选的,在上述一种5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物的制备方法中,包括以下步骤:
(1)在氩气保护条件下,将通式(Ⅱ)表示的化合物、对甲苯硫酚溶解在干燥的二氯甲烷中,然后在0℃下缓慢滴加三氟化硼乙醚,待反应液自然升至室温并反应完全后,加入三乙胺淬灭反应,加入饱和碳酸氢钠溶液,二氯甲烷萃取三次,合并有机相,经干燥、过滤、浓缩,得到通式(Ⅲ);
(2)将通式(Ⅲ)表示的化合物溶解在丙酮和水的混合溶液中,在0℃下加入三氯异氰尿酸至反应完全,然后加入乙酸乙酯,经洗涤、干燥、过滤、浓缩后得到通式(Ⅳ);
(3)将通式(Ⅳ)表示的化合物、2-(1-苯乙烯基)苯甲酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、4-二甲氨基吡啶溶解在干燥的二氯甲烷中,然后加入二异丙基乙胺,反应液在室温下搅拌反应至完全后,加入水淬灭反应,二氯甲烷萃取三次,合并有机相,经洗涤、干燥,过滤、浓缩,得到通式(I)。
本发明还公开了一种利用所述的5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物制备尿嘧啶核苷衍生物的方法,将5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物与尿嘧啶衍生物反应,制备得到尿嘧啶去氧核苷衍生物;
其中,尿嘧啶衍生物以通式(Ⅴ)表示,尿嘧啶去氧核苷衍生物以通式(VI)表示:
通式(V)和通式(VI)中R1为酰基,包括但不限于苯甲酰基、乙酰基、乙酰丙酰基、特戊酰基;R2为卤素原子氟或碘,乙烯基,乙炔基或被卤素、烷基、环烷基、芳环垸基、芳杂环基所取代的乙烯基、乙炔基。
优选的,在上述一种5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物制备尿嘧啶核苷衍生物的方法中,具体包括以下步骤:
(1)在氩气保护条件下,将通式(V)表示的化合物悬浮在无水乙腈中,加入N,O-双(三甲基硅烷基)三氟乙酰胺,在50℃下反应30min,备用;
(2)另取一个反应容器,在氩气保护条件下加入5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物、3A分子筛和无水乙腈,在室温条件下搅拌反应30min后加入步骤(1)制备得到的尿嘧啶溶液,继续室温搅拌15min后,在0℃条件下加入N-碘代丁二酰亚胺和三氟甲磺酸三甲基硅酯,反应液自然升至室温继续反应至完全,加入三乙胺淬灭反应,减压浓缩得到粗品,经硅胶柱层析得到通式(VI)。
本发明还提供了一种利用所述尿嘧啶核苷衍生物制备去氧氟尿苷的方法,所述去氧氟尿苷由尿嘧啶核苷衍生物经过甲醇钠水解得到。
优选的,在上述一种利用尿嘧啶核苷衍生物制备去氧氟尿苷的方法,包括以下步骤:
在氩气保护条件下,将尿嘧啶核苷衍生物溶解在干燥的甲醇中,然后在室温下加入甲醇钠反应至完全,继续加入盐酸调节pH至5-6,减压浓缩得到粗品,粗品用硅胶柱层析得到白色固体,即为去氧氟尿苷。
上述技术方案的有益效果是:
经由上述的技术方案可知,与现有技术相比,本发明用作上述反应原料的5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物作为糖基给体可以在催化量的路易斯酸三氟甲磺酸三甲基硅酯和N-碘代丁二酰亚胺的条件下进行活化,避免了传统的使用当量或过量的路易斯酸,反应体系温和,无其它副反应发生,反应高效,收率达到98%。
具体实施方式
下面将对本发明实施例中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。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明所应用的术语"烷基"是指有1~19个碳原子的直链或带支链的垸基:甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、庚基、辛基、壬基、癸基、十一垸基、十二烷基、十三烷基、十四烷基、十五垸基、十六垸基、十七垸基或十九垸基;
"环垸基"是指环丙基、环丁基、环戊基或环己基;
"链烯基"是指有3~19个碳原子的未取代或取代的链烯基,烯丙基、丁烯基、3-甲基-2-丁烯基、1-甲基-2-丙烯基、己烯基、癸烯基、十一碳烯基、十三碳烯基、十五碳烯基、十七碳烯基、十九碳烯基或2-苯基乙烯基;
"芳烷基"是指未取代或取代的芳垸基,例如苄基、1-苯基乙基、甲基苄基或苯乙基;
"芳基"是指未取代或取代的芳基,例如苯基、苯甲基、二甲苯基或乙基苯基;
"被卤素、垸基、环烷基、芳环垸基或芳杂环基所取代的乙烯基、乙炔基"是指1-氯乙烯基、2-溴乙烯基、1-氯-2-溴乙烯基、2-苯乙烯基、1-丙炔基、1-丁炔基、1-戊炔基、1-己炔基、3,3-二甲基-1-丁炔基、环戊乙炔基、环己乙炔基、苯乙炔基、3-苯基-1-丙炔基、吡啶-2-乙炔基或咪唑-2-乙炔基。
经实验证明,本发明路线操作简便,所获得的产品质量可靠、性能稳定。
下面通过具体实施例对本发明的技术方案进行说明。
实施例1
1-[2-(1-苯乙烯基)苯甲酸酯]-2,3-二-O-苯甲酰基-5-脱氧-D-呋喃核糖的制备
在氩气保护条件下,将2,3-二-0-苯甲酰基-5-脱氧-D-呋喃核糖甲苷(274mg,0.77mmol)、对甲苯硫酚(124mg,1.0mmol)溶解在6mL干燥的二氯甲烷中,然后在0℃下缓慢滴加三氟化硼乙醚(0.618mL,5mmol)。反应液自然升至室温并反应3小时,薄层色谱监测反应完全。加入三乙胺淬灭反应,加入饱和碳酸氢钠溶液,二氯甲烷萃取三次,合并有机相,无水硫酸钠干燥,过滤,滤液用旋转蒸发仪浓缩,硅胶柱层析(乙酸乙酯/石油醚=1/7)得到淡黄色液体296mg,收率86%。将上述所得的淡黄色液体溶解在13ml丙酮和3.3ml水的混合溶液中,然后在0℃下加入三氯异氰尿酸(153mg,0.66mmol)。反应液在0℃下反应1小时,薄层色谱监测反应完全。加入乙酸乙酯,依次用饱和碳酸氢钠溶液,水,各洗涤一次,有机相用无水硫酸钠干燥,过滤,滤液用旋转蒸发仪浓缩,硅胶柱层析(乙酸乙酯/石油醚=1/2.5)得到无色糖浆196mg,收率88%。将上述所得无色糖浆(184mg,0.53mmol)、2-(1-苯乙烯基)苯甲酸(132mg,0.58mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(186mg,0.95mmol)、4-二甲氨基吡啶(65mg,0.53mmol)溶解在5.4mL干燥的二氯甲烷中,然后加入二异丙基乙胺(0.266mL,1.59mmol),反应液在室温下搅拌1小时,薄层色谱监测反应完全。加入水淬灭反应,二氯甲烷萃取三次,合并有机相,饱和食盐水洗涤一次,无水硫酸钠干燥,过滤,滤液用旋转蒸发仪浓缩,硅胶柱层析(乙酸乙酯/石油醚=1/8)得到无色糖浆275mg(α/β=1/4),95%。
β-异构体数据:[α]D 25=1.19(c 0.24,CHCl3);1H NMR(400MHz,CDCl3)δ7.96(d,J=7.7Hz,3H),7.86(d,J=7.7Hz,2H),7.62–7.20(m,14H),6.26(s,1H),5.90(s,1H),5.46(d,J=4.8Hz,1H),5.26–5.23(m,2H),4.48–4.45(m,1H),1.28(d,J=6.5Hz,3H);13C NMR(100MHz,CDCl3)δ166.07,165.34,164.90,148.89,142.98,139.96,133.49,133.35,132.27,131.41,130.49,129.99,129.82,129.70,129.08,128.48,128.42,128.37,127.87,127.71,126.65,114.21,99.23,78.86,75.75,75.33,19.72;HRMS(ESI)calcd forC34H28O7Na[M+Na]+ 571.1727,found 571.1727。
实施例2
2',3'-二-O-苯甲酰基-5'-脱氧-5-氟-尿嘧啶核苷的制备
在氩气保护条件下将5-氟尿嘧啶(23mg,0.179mmol)悬浮在1.8mL无水乙腈中,加入N,O-双(三甲基硅烷基)三氟乙酰胺(96μl,0.364mmol),然后反应液在50℃下反应30分钟。另取一反应瓶,在氩气保护条件下加入1-[2-(1-苯乙烯基)苯甲酸酯]-2,3-二-O-苯甲酰基-5-脱氧-D-呋喃核糖(49mg,0.089mmol),3A分子筛360mg和1.8mL无水乙腈,该反应液在室温搅拌30分钟后加入新鲜制备的上述尿嘧啶溶液,继续室温搅拌15分钟后,在0℃下加入N-碘代丁二酰亚胺(30mg,0.134mmol)和三氟甲磺酸三甲基硅酯(8.0μl,0.045mmol)。反应液自然升至室温继续反应2小时,薄层色谱监测反应完全。加入三乙胺淬灭反应,直接减压浓缩得到粗品,硅胶柱层析(乙酸乙酯/石油醚=1/2.5)得到无色液体39mg,收率98%。
1H NMR(400MHz,CDCl3)δ9.10(s,1H),7.98(dJ=7.7,2H),7.9(d,J=7.8,2H),7.60–7.51(m,2H),7.49–7.31(m,5H),6.17(d,J=5.3Hz,1H),5.63(t,J=5.7Hz,1H),5.42(t,J=5.7Hz,1H),4.54–4.40(m,1H),1.59(d,J=6.4Hz,3H);13C NMR(101MHz,CDCl3)δ165.41,165.36,156.60,156.34,148.69,142.05,139.67,133.78,133.68,129.89,129.80,128.76,128.54,128.51,128.36,124.17,123.83,88.39,78.67,74.64,73.65,18.86;HRMS(ESI)calcd for C23H19N2O7FNa[M+Na]+:477.1069,found:477.1068。
实施例3
5'-脱氧-5-氟-尿嘧啶核苷(去氧氟尿苷)的制备
在氩气保护条件下,将2',3'-二-O-苯甲酰基-5'-脱氧-5-氟-尿嘧啶核苷(37mg,0.081mmol)溶解在0.8mL干燥的甲醇中,然后在室温下下甲醇钠(4.5mg,0.081mmol),反应液维持此温度继续反应1小时,薄层色谱监测反应完全。加入3N盐酸调pH为5-6,减压浓缩得到粗品,粗品用硅胶柱层析(二氯甲烷/甲醇=10/1)得到白色固体去氧氟尿苷19mg,收率95%。
[α]D 25=4.59(c0.14,CH3OH);1H NMR(400MHz,Methanol-d4)δ7.73(d,J=6.5Hz,1H),5.76(dd,J=4.0,1.5Hz,1H),4.16(dd,J=5.6,4.1Hz,1H),4.00(p,J=6.3Hz,1H),3.79(t,J=5.8Hz,1H),1.39(d,J=6.4Hz,3H);13C NMR(101MHz,Methanol-d4)δ158.14,157.88,149.49,141.65,139.33,124.93,124.58,90.37,79.68,74.48,73.66,17.36.;HRMS(ESI)calcdforC9H10N2O5FNa[M-H]-:245.0579,found:245.0578。
实施例4
1-[2-(1-苯乙烯基)苯甲酸酯]-2,3-二-O-乙酰基-5-脱氧-D-呋喃核糖的制备
在氩气保护条件下,将-2,3-二-O-乙酰基-5-脱氧-D-呋喃核糖(50.2mg,0.230mmol)、2-(1-苯乙烯基)苯甲酸(56.7mg,0.253mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(79.38mg,0.414mmol)、4-二甲氨基吡啶(28mg,0.230mmol)溶解在2.3mL干燥的二氯甲烷中,然后加入二异丙基乙胺(0.110mL,0.690mmol),反应液在室温下搅拌1小时,薄层色谱监测反应完全。加入水淬灭反应,二氯甲烷萃取三次,合并有机相,饱和食盐水洗涤一次,无水硫酸钠干燥,过滤,滤液用旋转蒸发仪浓缩,硅胶柱层析(乙酸乙酯/石油醚=1/7)得到无色糖浆75mg(α/β=1/6),77%。1H NMR(400MHz,CDCl3)δ7.90(d,J=7.4Hz,1H),7.54(t,J=7.1Hz,1H),7.44(t,J=7.4Hz,1H),7.35–7.21(m,6H),6.04(s,1H),5.85(s,1H),5.21(s,1H),5.09(d,J=4.6Hz,1H),4.90(dd,J=6.9,4.6Hz,1H),4.21-4.14(m,1H),2.07(s,3H),2.04(s,3H),1.15(d,J=6.4Hz,3H).13C NMR(100MHz,CDCl3)δ169.72,169.28,165.96,148.81,142.93,139.94,132.20,131.34,130.40,129.94,128.35,127.79,127.65,126.63,114.15,99.01,78.04,75.02,74.53,20.56,20.50,19.44.
实施例5
在氩气保护条件下将5-氟尿嘧啶(16mg,0.120mmol)悬浮在1.2mL无水乙腈中,加入N,O-双(三甲基硅烷基)三氟乙酰胺(62μl,0.240mmol),然后反应液在50℃下反应30分钟。另取一反应瓶,在氩气保护条件下加入1-[2-(1-苯乙烯基)苯甲酸酯]-2,3-二-O-苯甲酰基-5-脱氧-D-呋喃核糖(25mg,0.059mmol),3A分子筛240mg和1.2mL无水乙腈,该反应液在室温搅拌30分钟后加入新鲜制备的上述尿嘧啶溶液,继续室温搅拌15分钟后,在0℃下加入N-碘代丁二酰亚胺(20mg,0.090mmol)和三氟甲磺酸三甲基硅酯(5.42μl,0.030mmol)。反应液自然升至室温继续反应2小时,薄层色谱监测反应完全。加入三乙胺淬灭反应,直接减压浓缩得到粗品,硅胶柱层析(乙酸乙酯/石油醚=1/1)得到无色液体19mg,收率94%。
1H NMR(400MHz,CDCl3)δ9.46(s,1H),7.37(d,J=5.7Hz,1H),5.95(d,J=5.1Hz,1H),5.30(t,J=5.6Hz,1H),5.02(t,J=5.6Hz,1H),4.28–4.18(m,1H),2.13(s,3H),2.11(s,3H),1.46(d,J=6.4Hz,3H).13C NMR(100MHz,CDCl3)δ169.82,169.80,156.68,156.42,148.93,142.04,139.66,123.77,123.43,87.84,78.18,73.97,72.88,20.55,20.43,18.71.
本说明书中各个实施例采用递进的方式描述,每个实施例重点说明的都是与其他实施例的不同之处,各个实施例之间相同相似部分互相参见即可。对于实施例公开的装置而言,由于其与实施例公开的方法相对应,所以描述的比较简单,相关之处参见方法部分说明即可。
对所公开的实施例的上述说明,使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所示的这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (7)
3.根据权利要求2所述的5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物的制备方法,其特征在于,包括以下步骤:
(1)在氩气保护条件下,将通式(Ⅱ)表示的化合物、对甲苯硫酚溶解在干燥的二氯甲烷中,然后在0℃下缓慢滴加三氟化硼乙醚,待反应液自然升至室温并反应完全后,加入三乙胺淬灭反应,加入饱和碳酸氢钠溶液,二氯甲烷萃取三次,合并有机相,经干燥、过滤、浓缩,得到通式(Ⅲ);
(2)将通式(Ⅲ)表示的化合物溶解在丙酮和水的混合溶液中,在0℃下加入三氯异氰尿酸至反应完全,然后加入乙酸乙酯,经洗涤、干燥、过滤、浓缩后得到通式(Ⅳ);
(3)将通式(Ⅳ)表示的化合物、2-(1-苯乙烯基)苯甲酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、4-二甲氨基吡啶溶解在干燥的二氯甲烷中,然后加入二异丙基乙胺,反应液在室温下搅拌反应至完全后,加入水淬灭反应,二氯甲烷萃取三次,合并有机相,经洗涤、干燥,过滤、浓缩,得到通式(I)。
5.根据权利要求4所述的5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物制备尿嘧啶核苷衍生物的方法,其特征在于,具体包括以下步骤:
(1)在氩气保护条件下,将通式(V)表示的化合物悬浮在无水乙腈中,加入N,O-双(三甲基硅烷基)三氟乙酰胺,在50℃下反应30min,备用;
(2)另取一个反应容器,在氩气保护条件下加入5-脱氧-D-呋喃核糖1-[2-(1-苯乙烯基)苯甲酸酯]衍生物、3A分子筛和无水乙腈,在室温条件下搅拌反应30min后加入步骤(1)制备得到的尿嘧啶溶液,继续室温搅拌15min后,在0℃条件下加入N-碘代丁二酰亚胺和三氟甲磺酸三甲基硅酯,反应液自然升至室温继续反应至完全,加入三乙胺淬灭反应,减压浓缩得到粗品,经硅胶柱层析得到通式(VI)。
6.一种利用权利要求4所述的尿嘧啶核苷衍生物制备去氧氟尿苷的方法,其特征在于,所述去氧氟尿苷由尿嘧啶核苷衍生物经过甲醇钠水解得到。
7.根据权利要求6所述的利用尿嘧啶核苷衍生物制备去氧氟尿苷的方法,其特征在于,包括以下步骤:
在氩气保护条件下,将尿嘧啶核苷衍生物溶解在干燥的甲醇中,然后在室温下加入甲醇钠反应至完全,继续加入盐酸调节pH至5-6,减压浓缩得到粗品,粗品用硅胶柱层析得到白色固体,即为去氧氟尿苷。
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