CN101735296A - 一种氟达拉滨的制备方法 - Google Patents

一种氟达拉滨的制备方法 Download PDF

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CN101735296A
CN101735296A CN200910244892A CN200910244892A CN101735296A CN 101735296 A CN101735296 A CN 101735296A CN 200910244892 A CN200910244892 A CN 200910244892A CN 200910244892 A CN200910244892 A CN 200910244892A CN 101735296 A CN101735296 A CN 101735296A
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fludarabine
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alcohol
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CN101735296B (zh
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宋洪海
林大勇
彭啸
杨民文
马春磊
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Tianjin Weijie Technology Co Ltd
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Abstract

一种氟达拉滨的制备方法。其是以2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤作为原料，以饱和脂肪醇作为溶剂，以氨水作为反应试剂，在-5～15℃的温度下反应24～48小时，然后经过抽滤而得到粗品，最后将粗品进行重结晶而得到氟达拉滨。本发明提供的氟达拉滨的制备方法是以饱和脂肪醇作为溶剂，由于没有使用含氯的溶剂，所以不会对环境造成污染。另外，该制备方法相对已有技术还具有反应时间短，原料的成本低、产物纯度高且操作简单等优点，因此适于工业化生产。

Description

一种氟达拉滨的制备方法
技术领域
本发明属于药品制备技术领域，特别是涉及一种氟达拉滨的制备方法。
背景技术
氟达拉滨的化学名称为9-β-D-阿拉伯呋喃糖-2-氟腺苷，其是一种抗肿瘤药物。已有文献中报道过该药物的多种制备方法，其中美国专利第5602246号中就公开了一种氟达拉滨的制备方法，该方法是以2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤和无水乙醇(80ml/g)作为原料，在0～5℃的温度下反应超过96小时，然后浓缩，之后用氯仿进行提取，最后重结晶后而得到纯品。这种制备方法的缺点是反应时间长；由于使用了含氯溶剂，所以会造成环境污染；另外需要浓缩处理，所以操作过程复杂。美国专利第5712099号中公开了另一种氟达拉滨的制备方法，该方法是使用酶和2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤作为原料，经反应而制备成氟达拉滨，该方法的缺点是酶价格高(130U/mg)，因此不适于工业化生产。
发明内容
为了解决上述问题，本发明的目的在于提供一种能够克服上述现有技术缺点的氟达拉滨的制备方法。
为了达到上述目的，本发明提供的氟达拉滨的制备方法是以2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤作为原料，以饱和脂肪醇作为溶剂，以氨水作为反应试剂，在-5～15℃的温度下反应24～48小时，然后经过抽滤而得到粗品，最后将粗品进行重结晶而得到氟达拉滨。
所述的氨水与2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤的用量比为5～20ml∶1g。
所述的饱和脂肪醇与2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤的用量比为5～20ml∶1g。
所述的饱和脂肪醇是分子式为ROH的化合物，其中R为碳原子数为1到4的直链烷基。
所述的饱和脂肪醇选自甲醇、乙醇和丙醇中的一种。
所述的重结晶所使用的溶剂为乙醇和水的混合溶剂，乙醇和水的体积比为V乙醇∶V水＝3∶1。
所述的反应温度为-5～15℃。
本发明提供的氟达拉滨的制备方法是以饱和脂肪醇作为溶剂，由于没有使用含氯的溶剂，所以不会对环境造成污染。另外，该制备方法相对已有技术还具有反应时间短，原料的成本低、产物纯度高且操作简单等优点，因此适于工业化生产。
具体实施方式
实施例1：
在50ml的反应瓶中加入10ml乙醇和10ml氨水并混合均匀，然后将上述混合液冷却到5℃，之后加入1g(2.43mmol)2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤，在5℃的温度下反应24小时，待TLC或者HPLC检测结果表明反应完全后，将上述反应液进行抽滤而得到0.66g粗品，粗品收率为99％，母液无需回收，然后将滤饼用15ml乙醇和5ml水作为溶剂进行重结晶而得到0.58g白色固体状氟达拉滨，该产物的收率为84％，HPLC含量≥99.8％，主要杂质HPLC含量：0.02％、0.1％、0.01％和0.01％。
实施例2：
在500ml的反应瓶中加入100ml乙醇和200ml氨水并混合均匀，然后将混合液冷却到15℃，之后加入10g(24.3mmol)2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤，在15℃的温度下反应36小时，待TLC或者HPLC检测结果表明反应完全后，将上述反应液进行抽滤而得粗品6.1g粗品，粗品收率为90％，母液无需回收，然后将滤饼用120ml乙醇和40ml水作为溶剂进行重结晶而得到5.1g白色固体状氟达拉滨，该产物的收率为75％，HPLC含量99.2％，主要杂质HPLC含量：0.1％、0.2％、0.2％和0.1％。
实施例3：
在250ml的反应瓶中加入100ml乙醇和50ml氨水并混合均匀，然后将混合液冷却到10℃，然后加入10g(24.3mmol)2-氟-9-β-D-(2′，3′，5′-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤，在10℃的温度下反应36小时，待TLC或者HPLC检测结果表明反应完全后，将上述反应液进行抽滤而得粗品5.8g粗品，粗品收率为86％，母液无需回收，然后将滤饼用100ml乙醇和33.3ml水作为溶剂进行重结晶而得到4.8g白色固体状氟达拉滨，该产物的收率为72％，HPLC含量99.5％，主要杂质HPLC含量：0.1％、0.2％、0.1％和0.08％。

Claims (7)

1.一种氟达拉滨的制备方法，其特征在于：所述的氟达拉滨的制备方法是以2-氟-9-β-D-(2’，3’，5’-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤作为原料，以饱和脂肪醇作为溶剂，以氨水作为反应试剂，在-5～15℃的温度下反应24～48小时，然后经过抽滤而得到粗品，最后将粗品进行重结晶而得到氟达拉滨。
2.根据权利要求1所述的氟达拉滨的制备方法，其特征在于：所述的氨水与2-氟-9-β-D-(2’，3’，5’-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤的用量比为5～20ml∶1g。
3.根据权利要求1所述的氟达拉滨的制备方法，其特征在于：所述的饱和脂肪醇与2-氟-9-β-D-(2’，3’，5’-三-O-乙酰基阿拉伯呋喃糖基)腺嘌呤的用量比为5～20ml∶1g。
4.根据权利要求3所述的氟达拉滨的制备方法，其特征在于：所述的饱和脂肪醇是分子式为ROH的化合物，其中R为碳原子数为1到4的直链烷基。
5.根据权利要求4所述的氟达拉滨的制备方法，其特征在于：所述的饱和脂肪醇选自甲醇、乙醇和丙醇中的一种。
6.根据权利要求1所述的氟达拉滨的制备方法，其特征在于：所述的重结晶所使用的溶剂为乙醇和水的混合溶剂，乙醇和水的体积比为V乙醇∶V水＝3∶1。
7.根据权利要求1所述的氟达拉滨的制备方法，其特征在于：所述的反应温度为-5～15℃。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102911230A (zh) * 2012-04-16 2013-02-06 淮海工学院 一种氟达拉滨的合成方法
CN105998047A (zh) * 2016-05-09 2016-10-12 中山大学肿瘤防治中心 一种治疗癌症的新联合用药方案

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* Cited by examiner, † Cited by third party
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US5602246A (en) * 1992-11-25 1997-02-11 Schering Aktiengesellschaft Process for the preparation of fludarabine or fludarabine phosphate from guanosine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102911230A (zh) * 2012-04-16 2013-02-06 淮海工学院 一种氟达拉滨的合成方法
CN105998047A (zh) * 2016-05-09 2016-10-12 中山大学肿瘤防治中心 一种治疗癌症的新联合用药方案

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