CN107011382A - 一种替诺福韦前药及其制备方法 - Google Patents
一种替诺福韦前药及其制备方法 Download PDFInfo
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- CN107011382A CN107011382A CN201610055098.XA CN201610055098A CN107011382A CN 107011382 A CN107011382 A CN 107011382A CN 201610055098 A CN201610055098 A CN 201610055098A CN 107011382 A CN107011382 A CN 107011382A
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- tenofovir
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
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- YHMFXCDRFAPFHZ-UHFFFAOYSA-N propan-2-yl propanoate hydrochloride Chemical compound Cl.CCC(=O)OC(C)C YHMFXCDRFAPFHZ-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及全新结构的替诺福韦前药及其制备方法。
Description
一、技术领域
本发明涉及全新结构的替诺福韦前药及其制备方法。
二、背景技术
替诺福韦是美国Gilead Sciences公司生产一种新型核苷酸逆转录酶抑制剂,可有效的抑制多种病毒。其药用形式为替诺福韦富马酸二吡喃酯。该药物已被世界卫生组织(WHO)推荐为抗艾滋病的一线药物。但是替诺福韦二吡喃磷酸酯在水解释放药物的同时会代谢产生甲醛,并且二吡喃酯类结构的脂溶性仍然有限,从而影响药物吸收。
CN1810616用长链脂肪烃作为侧链制备了替诺福韦单磷酸酯,但是由于磷酸基团仍然剩余一个酸性羟基,所以从本质上和替诺福韦二吡喃酯并没有改变其生物利用度和副作用。结构通式如下,其中x=0-8,y=1-20.
CN102786在上述专利的基础之上将一个羟基用L-丙氨酸异丙酯形成磷酰胺而得到替诺福韦双磷酸衍生物。但是长脂肪烃链仅仅是为了增加脂溶性,并无任何潜在的生物学活性。结构通式如下:其中m=0-4,n=12-16.
CN103732594制备了替诺福韦和L-丙氨酸异丙酯以及苯酚形成二磷酸衍生物,然后与富马酸成盐并进行了相关药理活性研究。但是所制备结果中代谢产物含有苯酚,具有极大的肝毒性。其结构式如下
CN103665043在替诺福韦二吡喃酯的基础上将一个吡喃酯换为苯酚成酯,所产生问题仍然是代谢产生肝毒性极大的苯酚。其中Ar=2,6位二取代或4位单取代苯或单独为萘环。二取代的包括甲基,单取代基包括卤素,三氟甲基,乙酰氧基,甲氧基。R1和R2为C1-6烷基或C3-7环烷烃。
CN103224530将替诺福韦与长链脂肪烃以及各种不同氨基酸形成二酯,同样的问题是长链脂肪侧链有些对人体有副作用,有些则不具备生物学活性,只是单纯为了增加脂溶性。通式如下:其中m=1,n=14,R=L-丙氨酸形成的异丙醇酯、叔戊醇酯、正丁醇酯、环己醇酯、乙醇酯。
三、发明内容
鉴于上述分析,为了克服现在替诺福韦存在的体内代谢释放甲醛以及提高药物脂溶性和改善生物利用度。本发明设计了全新的替诺福韦二磷酸衍生物以及简单可行的制备方法。
为了实现上述目的,本发明采用如下技术方案:
①将替诺福韦和有机胺以及另一反应物分散到有机溶剂中,加热到80℃以上,向上述体系中滴加缩合剂,滴加完毕后加热到100℃反应。所用胺为三乙胺,有机溶剂为NMP,体积为替诺福韦质量的10-15mL/g。缩合剂为DCC。
②反应结束之后采用减压蒸馏得到深棕色黏状物,随后分散到水中加入碱成盐。减压蒸馏温度为120-140℃,真空度为10-300Pa。成盐所用溶液为25%NaOH溶液,体积为减压蒸干油状物的1.5-3mL/g。
③在分液漏斗中用有机试剂洗上述盐溶液若干次。随后分出水层并过滤出不容物。洗涤水层所用有机试剂为乙酸乙酯或二氯甲烷,体积为水体积的1-3倍。
④所得水层用无机酸调pH后析出固体并抽滤,滤饼随后用甲醇打浆然后抽滤,用甲醇洗涤滤饼数次后自然晾干得到替诺福韦单磷酸衍生物。甲醇体积为粗品质量的10-15ml/g。调pH所用酸为35%盐酸水溶液,pH调至3-4之间。
⑤所得替诺福韦单磷酸衍生物分散到有机试剂中,用酰氯氯代,随后与另一分子形成替诺福韦双磷酸衍生物,或直接采用缩合剂缩合也可。有机溶剂可以是环丁砜、DMF、NMP、DMSO。氯代试剂为二氯亚砜、草酰氯。缩合剂为HATU、HOBT。
⑥上述反应溶液蒸干得到的油状物用硅胶拌样经过柱层析分离后得到替诺福韦双磷酸衍生物的光学混合物。
四、具体实施方式
以下实施例是对本发明的进一步说明,但并补限制本发明。
实施例1:MWX-2的制备
替诺福韦4.32g和L-(-)-薄荷醇2.34g溶于54mL事先预热到85℃的NMP中,然后加入1.2当量三乙胺并升温到100℃。1.63当量DCC用20mL NMP溶解后缓慢滴加,滴毕之后保持100℃反应16h,冷却到室温,抽滤除去不溶物,滤饼用21mL水洗,合并滤液减压蒸馏直至变成粘稠物,加33mL水,然后用25%NaOH溶液调pH到11,加硅藻土抽滤,滤饼用6.0mL水洗,水层用乙酸乙酯40.0mL洗,分出水层后用浓盐酸调pH到3,抽滤,滤饼用甲醇30mL打浆后抽滤,干燥得3.5g目标化合物MWX-1。MS(ESI):m/z:426.2[M+H]+
将按上述方法制得的MWX-1称取3.18g,与3当量三乙胺溶解在DMF∶NMP=2∶1的30mL混合溶剂中,加入HATU 1.0g,HOBT 0.35g,室温混合1h后,在冰盐浴下缓慢滴加L-丙氨酸异丙酯盐酸盐1.84g溶于10mL二氯甲烷溶液,滴毕之后室温继续搅拌1.5h。加水200mL稀释后用DCM 50mL X3萃取,分出有机层,无水硫酸钠干燥,浓缩,剩余物经过硅胶柱层析分离得1.3g目标化合物MWX-2。MS(ESI)m/z:539.3[M+H]+
实施例2:MWX-4的制备
将替诺福韦4.0g分散到12mL环丁砜中,加入2.1当量草酰氯后60℃加热2h。冷却到室温随后加入60mL二氯甲烷,-10℃下缓慢滴加L-丙氨酸异丙酯盐酸盐2.32g和1.6mL三乙胺、20mL二氯甲烷的混合溶液,搅拌1.0h后再滴加6.0g维生素E溶于30mL二氯甲烷溶液,滴毕,继续搅拌2h。将反应液倒入分液漏斗中,用水洗有机层2次。分出有机层后加入无水硫酸钠固体干燥过夜,过滤除去干燥剂后,浓缩,经过硅胶柱层析分离得到2.3g目标化合物MWX-4。MS(ESI):m/z:813.4[M+H]+
实施例3:MWX-6的制备
将替诺福韦4.0g与维生素A 4.0g同溶于50mL NMP,100℃下滴加1.7当量DCC和3当量三乙胺混合的30mL NMP溶液,滴毕,保持该温度4h。随后冷却到60℃滴加1.1当量二氯亚砜,滴毕后继续搅拌0.5h并冷却到0℃,随后再加入2.32g L-丙氨酸异丙酯盐酸盐的30mLDCM溶液,滴后继续搅拌1h。反应结束后将反应液转移至分液漏斗中,水洗有机层,有机层用无水硫酸钠干燥过夜。过滤,浓缩,经硅胶柱层析分离得到化合物4.1g目标化合物MWX-6。MS(ESI)m/z:669.4[M+H]+
实施例4:MWX-2富马酸盐的制备
将0.2g富马酸溶解在丙酮中加热回流直到澄清。0.93g的MWX-2溶于丙酮溶液在回流下滴加到上述溶液中,滴毕,关闭加热继续搅拌冷却到室温。将析出固体抽滤,干燥得到1.02g目标化合物MWX-2-A。
实施例5:MWX-4富马酸盐的制备
将0.05g富马酸溶于异丙醇当中加热回流到澄清,随后关闭加热直接加入0.35g的MWX-4。搅拌冷却到室温将析出固体抽滤,用少量二氯甲烷洗滤饼,干燥得到0.32g目标化合物MWX-4-A。
实施例6:MWX-6富马酸盐的制备
将0.25g富马酸溶于乙腈中加热回流到澄清,随后将1.15g的MWX-6溶于乙腈中,在回流下缓慢滴加到上述溶液中,滴毕,关闭加热搅拌冷却至室温,抽滤,用二氯甲烷洗滤饼,干燥,得到1.23g目标化合物MWX-6-A。
Claims (17)
1.一种如通式(I)所示的化合物或其药用盐。
其中:R独立的选自C5-C30直链或环状为母核的天然产物,包括天然或半合成的糖类,醇类,维生素。
2.根据权利要求1所述结,其特征是所用糖类为单糖或多糖,维生素为脂溶性维生素。
3.根据权利要求2所述,其特征是糖类结构如下:单糖包括母核为C3-C6的环状或直链的丙糖,丁糖,核糖,阿拉伯糖,木糖,鼠李糖,葡萄糖,呋喃糖,甘露糖,阿洛糖。多糖包括麦芽糖,乳糖,纤维二糖,蔗糖。脂溶性维生素包括A,D,E,K。天然醇类包括L-(-)-薄荷醇,白藜芦醇,银杏叶聚戊烯醇,黄酮醇。
4.根据权利要求1所述,其特征是制备过程中缩合反应步骤是在单一有机溶剂中加入有机胺、缩合剂以及替诺福韦。加热回流得到替诺福韦单磷酸酯或单磷酰胺。
5.根据权利5所述,其特征是所用有机溶剂沸点为100-250℃。缩合反应温度为50-100℃。所用体积为替诺福韦质量5-30倍(ml/g)。
6.根据权利要求5所述,其特征是所用溶剂包括N,N-二甲基甲酰胺(DMF),N-甲基吡咯烷酮(NMP),二甲基亚砜(DMSO),二氧六环,甲苯,二甲苯。
7.根据权利要求4所述,其特征是所用缩合剂包括下述种类,N,N-二环己基碳二酰亚胺(DCC),苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP),2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI),6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU),1-羟基苯并三唑(HOBT)。所用质量为反应物摩尔数的0.5-3倍量。
8.根据权利要求7所述要求缩合剂首选DCC。
9.根据权利要求6所述溶剂首选NMP。
10.根据权利要求1所述,其特征是制备替诺福韦单磷酸衍生物反应过程中所用有机胺包括三乙胺,N,N-二异丙基已胺,二乙胺。
11.根据权利要求1所述,其特征是蒸馏过程采用减压蒸馏,真空度为10-300Pa。成盐所用碱为NaOH,KOH,浓度为5-30%水溶液。萃取试剂为二氯甲烷,乙酸乙酯,用量为减压蒸馏得到油状物质量的1-3ml/g。减压蒸馏温度为100-140℃。
12.根据权利要求1所述,其特征是替诺福韦单磷酸衍生物酰化所用溶剂为二氯亚砜,草酰氯,三氯氧磷,用量为替诺福韦摩尔比的0.5-1.5当量。
13.根据权利要求1所述,其特征是调pH所用为盐酸、硫酸、冰醋酸、磷酸,浓度为5-35%水溶液,调至pH范围在1-4之间。
14.根据权利要求1所述,其特征是替诺福韦单磷酸衍生物的制备采用NMP做溶剂,三乙胺为缚酸剂,DCC做缩合剂80-100℃下加热16h制得,成盐所用碱为NaOH,调pH所用酸为盐酸。三乙胺用量为替诺福韦摩尔数的1.0-1.8当量,DCC为1.0-2.0当量。
15.根据权利要求1所述,其特征是替诺福韦单磷酸衍生物采用二氯亚砜氯代或用HATU与HOBT与另一分子缩合得到替诺福韦双磷酸衍生物粗品,而后经过硅胶柱分离得到替诺福韦光学异构体混合物。HATU与HOBT用量为替诺福韦摩尔数的0.5-1.5倍。
16.根据权利要求1所述,其特征是药用盐包括富马酸盐、盐酸盐、硫酸盐、硝酸盐、磷酸盐。成盐所用化合物结构如下:
。
17.根据权利要求16所述,其特征是成盐所用有机溶剂包括丙酮、已经、异丙醇、乙醇、甲醇、乙酸乙酯、乙醚。
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CN108623632A (zh) * | 2018-08-17 | 2018-10-09 | 上海麦步医药科技有限公司 | 一种替诺福韦艾拉酚胺的制备方法 |
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CN111116655B (zh) * | 2019-12-30 | 2022-10-25 | 天津天士力圣特制药有限公司 | 一种高光学纯度替诺福韦苄酯膦酰胺前体药物的制备方法 |
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