CN105693785B - 合成1,3,4,6-四乙酰基-l-古罗糖的方法 - Google Patents
合成1,3,4,6-四乙酰基-l-古罗糖的方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H13/06—Fatty acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明公开了一种合成1,3,4,6‑四乙酰基‑L‑古罗糖的方法,该方法采用已知化合物II为原料,经过伯羟基硅保护、苄基保护、脱硅保护基、伯羟基氧化为醛、脱乙缩醛保护、多羟基乙酰化、脱苄基保护等步骤得到化合物1,3,4,6‑四乙酰基‑L‑古罗糖。本发明路线简短,总收率高,操作简便、条件易控,不涉及昂贵或剧毒试剂的使用,可进行克级以上大量合成,易于工业化生产。
Description
技术领域
本发明涉及化合物制备技术领域,特别涉及博来霉素A2二糖单位中L-古罗糖的制备技 术领域,更具体地是指一种合成1,3,4,6-四乙酰基-L-古罗糖的方法。
背景技术
博来霉素是由轮枝链霉菌产生的一类结构相近的糖肽类抗生素,可以通过介导肿瘤细胞 DNA和RNA的氧化裂解而被用于抗肿瘤,临床上常用于霍奇金氏淋巴瘤、鳞状细胞瘤等。 此外,由于博来霉素能特异性的靶向人和动物的肿瘤细胞而在临床上被用作肿瘤诊断药。从 结构上看,博来霉素分子由六肽以及二糖部分组成,其中二糖部分被认为不仅可以形成分子 空腔辅助氧化裂解的过程,而且在细胞表面识别发挥重要作用。Zhiqiang Yu等人则用实验证 明了博来霉素的二糖部分是博来霉素能选择性靶向肿瘤细胞的原因。这使得将这个二糖运用 于靶向抗肿瘤药的设计成为可能。
在糖化学中,D型单糖作为糖合成的构建模块在自然界广泛存在,因而便宜而易得。而 L型单糖作为糖的组装模块由于稀少而价格昂贵,因此,如何大量,高收率的合成L型糖成 为糖化学的重点和难点。
博来霉素二糖部分为2-O-(3-胺甲酰基-α-D-甘露糖)-L-古罗糖(图1),即:3位胺甲酰基 取代的α-D甘露糖通过α-1,2糖苷键与L-古罗糖2位相连接。L-古罗糖作为博来霉素二糖部 分重要的构建单元,其合成方法已有诸多报道。主要有以下几种:(1)由DaleL.Boger等 (J.Am.Chem.SOC.1994,116,5647-5656),Oshitari,Tetsuta等人(TetrahedronLetters 1994,35 (35),6493-6494.)报道的以D-甘露糖为原料,通过将甘露糖5位构象翻转转化而来;
(2)由González,Francisco Santoyo等人(Carbohydrate Research 1990,202(0),33-47.), 以及由Ding,Xianglan等人(Carbohydrate Research 1996,286(0),161-166.)报道的以D-葡萄糖 为原料,通过将葡萄糖1位和6位的氧化态互换而来;
(3)Kobori,Yoshihiro等人(J.Org.Chem.1992,57(22),5899-5907.)用酶法合成古罗糖;
(4)由Alessandro Dondoni(J.Org.Chem.1997,62,6261-6267)等人报道的以L-木糖为原料 经过一系列转化得到L-古罗糖;
(5)由Wen-Bin Yang(Tetrahedron58(2002)253-259)等人报道的以葡萄糖酸1,5-内酯 为原料经过保护、还原、选择性脱丙酮叉等一系列转化得到L-古罗糖。
(6)中国专利ZL201410059416.0报道的葡萄糖醛酸内酯为原料,经过丙酮叉保护、苄 基保护、内酯还原、半缩醛羟基保护、脱丙酮差保护、半缩醛还原、脱半缩醛保护、乙酰基保护,脱苄基保护等一系列转化得到L-古罗糖。
这些已报道的合成方法大多合成路线较长,需要用到较昂贵的原料或者化学试剂,且对 实验操作者的要求较高,不易实现放大生产。
发明内容
本发明的主要目的就是针对以上存在的问题与不足,提供一种克级以上规模合成1,3,4,6- 四乙酰基-L-古罗糖的方法,该方法具有合成路线简短、操作简便、成本低、产率高、易于工 业化生产的优点。
为了实现上述目的,本发明采用的技术方案是:
一种合成1,3,4,6-四乙酰基-L-古罗糖的方法,包括以下具体步骤:
a、用叔丁基二甲基氯硅烷(TBSCl)选择性保护化合物Ⅱ的伯羟基得到化合物Ⅲ;
b、以氢化钠为碱,使用苄基保护化合物Ⅲ的羟基得到化合物Ⅳ;
c、用四丁基氟化铵(TBAF)脱除硅保护基得到化合物Ⅴ;
d、通过戴斯马丁氧化或斯文氧化将化合物Ⅴ的伯羟基氧化为醛,得到化合物Ⅵ;
e、在酸性条件下脱除乙缩醛保护基使其自动闭环得到苄基取代的吡喃糖Ⅷ;
f、以吡啶做溶剂,用醋酐使吡喃糖Ⅷ的羟基乙酰化,得到化合物Ⅸ;
g、用催化氢化的方法脱除化合物Ⅸ的苄基保护,得到目标产物Ⅰ;其中:
所述步骤a中使用的溶剂为二氯甲烷或N,N-二甲基甲酰胺(DMF),TBSCl与化合物Ⅱ 的摩尔比为1:1~1.5:1,所用碱为三乙胺或咪唑,反应温度0~25℃,反应时间为6~18h。
所述步骤b中所用溶剂为DMF或四氢呋喃(THF),所用碱为氢化钠,苄基化试剂为溴化苄,反应温度为0~40℃,反应时间6~24h;反应结束后,使用水淬灭反应。
所述步骤c中反应溶剂为THF,TBAF与化合物Ⅳ的摩尔比为1:1~3:1,反应温度0~40℃,反应时间为2~12h;反应结束后,通过使用石油醚、乙酸乙酯、二氯甲烷、甲苯中的 一种或几种打浆,得到白色固体即化合物Ⅴ。
所述步骤d中所用氧化方法为戴斯马丁氧化或斯文氧化;反应结束后通过硅胶柱层析纯 化得到化合物Ⅵ。
所述步骤e中所用酸为浓度0.1mol/L~2mol/L的盐酸或硫酸,反应温度110~140℃, 反应时间为2~12h;反应结束后冷却至室温,继续搅拌12~36h;加入碳酸钡粉末或阴离子 交换树脂至反应液中性,抽滤,旋干滤液,将所得粘稠液体直接投入下一步反应。
所述步骤f中所用的溶剂为吡啶,所用乙酰化试剂为醋酐,醋酐与化合物Ⅷ的摩尔比为 5~20:1,反应温度为0~40℃,反应时间为6~24h;反应结束后,于-15℃~10℃下,用1M~ 3M盐酸溶液调反应液pH至酸性后用乙酸乙酯萃取2~3次,合并的有机相经水洗,饱和食 盐水洗并干燥,浓缩溶剂后柱层析纯化得到混合物Ⅸ。
所述步骤g中催化氢化所用的催化剂为5~20%的Pd/C或Pd(OH)2/C,所用的溶剂为甲 醇、乙醇或乙酸乙酯;反应温度为15~50℃,反应时间为2~36h;反应结束后,过滤反应液, 滤液浓缩后直接得到目标产物Ⅰ即1,3,4,6-四乙酰基-L-古罗糖。
其具体合成路线为:
本发明采用的原料为已知化合物Ⅱ,可由已经实现工业化生产D-山梨醇一步制得,因而 该原料廉价易得。本发明路线简短,总收率达54%,操作简便、条件易控,不涉及昂贵或剧 毒试剂的使用,可进行克级以上大量合成,易于工业化生产。
附图说明
图1为背景技术描述的博来霉素二糖部分为2-O-(3-胺甲酰基-α-D-甘露糖)-L-古罗糖的 示意图;
图2为本发明实施例7所得产物1H-NMR谱的截图。
具体实施方式
为了能够更清楚地理解本发明的技术内容,现结合实施例进一步说明如下:
实施例1
化合物Ⅲ的制备
28.8g化合物Ⅱ溶于130ml二氯甲烷,冰水浴条件下,加入16.5g咪唑、20.1gTBSCl, 室温搅拌15h,依次用水、饱和食盐水洗,无水硫酸钠干燥,硅胶柱色谱得无色粘稠液体, 即化合物Ⅲ38.1g,收率89%。
1H NMR(400MHz,CDCl3)δ4.81(q,J=5.0Hz,1H),4.74(q,J=5.1Hz,1H),4.15(d,J= 12.6Hz,1H),4.00–3.92(m,1H),3.91–3.84(m,2H),3.83–3.74(m,2H),3.56(d,J=8.8Hz, 1H),3.51(s,1H),2.51(d,J=7.5Hz,1H),1.41(t,J=4.9Hz,6H),0.90(s,9H),0.08(s,6H)。
实施例2
化合物Ⅳ的制备
N2气流下,5.2g氢化钠悬浮于70ml THF,冰水浴条件下,38.1g化合物Ⅲ溶于160mlTHF后加入,缓慢滴加14.2ml溴化苄,室温搅拌12h。加水淬灭反应,乙酸乙酯萃取三次, 合并有机相,依次用水、饱和食盐水洗,无水硫酸钠干燥。硅胶柱色谱得白色固体,即化合 物Ⅳ44.3g,收率92%。
1H NMR(400MHz,CDCl3)δ7.38–7.27(m,5H),4.78(d,J=11.5Hz,1H),4.74(q,J=5.2 Hz,1H),4.67(q,J=5.0Hz,1H),4.54(d,J=11.5Hz,1H),4.14(d,J=12.6Hz,1H),3.94(d,J= 10.9Hz,1H),3.89–3.78(m,3H),3.77–3.67(m,2H),3.48(s,1H),1.41(d,J=5.1Hz,3H),1.35 (d,J=5.0Hz,3H),0.91(s,9H),0.07(s,6H)。
实施例3
化合物Ⅴ的制备
化合物Ⅳ33.6g溶于THF,分批加入39.5g TBAF·3H2O,室温搅拌6h,加水、乙酸 乙酯分液,水相用乙酸乙酯萃取两次,合并与有机相,依次用饱和氯化铵水溶液、饱和食盐 水洗,无水硫酸钠干燥。抽滤,滤液旋干,加入石油醚搅拌2h,抽滤得白色固体,即化合物 Ⅴ19.9g,收率74%。
1H NMR(400MHz,CDCl3)δ7.41–7.27(m,5H),4.79(q,J=5.1Hz,1H),4.71–4.62(m,2H),4.54(d,J=11.4Hz,1H),4.13(dd,J=12.6,0.9Hz,1H),3.91–3.80(m,3H),3.80–3.70(m, 3H),3.49(s,1H),2.01(dd,J=8.9,3.1Hz,1H),1.41(d,J=5.1Hz,3H),1.35(d,J=5.1Hz,3H)。
实施例4
化合物Ⅵ的制备
1.0g化合物Ⅴ溶于10ml二氯甲烷中,冰水浴条件下,分批加入2.0g戴斯马丁氧化剂, 搅拌10min,加入0.06ml水,室温搅拌40min。旋干溶剂,加入硫代硫酸钠饱和溶液/饱和碳酸氢钠溶液(1:1)混合溶液、乙酸乙酯,分液,水相乙酸乙酯萃取两次,合并有机相, 依次用饱和碳酸氢钠溶液、饱和食盐水洗,无水硫酸镁干燥。硅胶柱色谱纯化得淡黄色粘稠 液体1.0g,含杂质,直接投入下一步。
1H NMR(400MHz,CDCl3)δ9.81(d,J=1.4Hz,1H),7.40–7.28(m,5H),4.79–4.72(m,2H),4.66(q,J=5.1Hz,1H),4.43(d,J=11.6Hz,1H),4.29(dd,J=8.7,1.4Hz,1H),4.14(dd,J= 12.6,1.3Hz,1H),3.92(dd,J=8.7,1.9Hz,1H),3.85(dd,J=12.7,2.0Hz,1H),3.72(t,J=1.5Hz, 1H),3.52(d,J=1.4Hz,1H),1.41(d,J=5.1Hz,3H),1.32(d,J=5.1Hz,3H)。
实施例5
化合物Ⅸ的制备
所得粘稠液体溶于3ml二氧六环,加入10ml 0.1mol/L的硫酸,120℃回流6h,室温搅拌16h。加入碳酸钡粉末中和至pH为7,抽滤,滤液旋干。
将所得粘稠液体溶于10ml吡啶,加入2.9ml醋酐,室温搅拌12h。反应液倒入50ml冰水中,2mol/L的盐酸中和至pH小于7。乙酸乙酯萃取三次,合并有机相,依次用饱和碳 酸钠溶液、水、饱和食盐水洗,无水硫酸钠干燥,硅胶柱色谱纯化得淡黄色粘稠液体,即化 合物Ⅸ1.0g,步骤e、f、g三步总收率74%。
1H NMR(400MHz,CDCl3)δ7.37–7.27(m,5H),5.93(d,J=8.3Hz,1H),5.49(t,J=3.6Hz, 1H),4.99(dd,J=3.9,1.4Hz,1H),4.66(d,J=11.9Hz,1H),4.53(d,J=11.9Hz,1H),4.37–4.27 (m,1H),4.15(dd,J=11.5,5.9Hz,1H),4.07(dd,J=11.5,7.1Hz,1H),3.68(dd,J=8.3,3.4Hz, 1H),2.15(s,3H),2.12(s,3H),2.09(s,3H),2.05(s,3H)。
实施例6
目标产物Ⅰ的制备
1.4g化合物Ⅸ溶于60ml乙酸乙酯中,换氮气保护,往反应液中加入0.6g 10%Pd/C,再 次换氮气保护,用H2置换反应体系的N2,室温反应过夜。过滤出反应体系的固体,滤液浓 缩,硅胶柱色谱纯化得到白色泡沫状固体,即目标产物Ⅰ0.85g,收率94%。
1H NMR(400MHz,CDCl3)δ5.85(d,J=8.5Hz,1H),5.35(t,J=3.6Hz,1H),5.02(dd,J=3.8, 1.5Hz,1H),4.33–4.26(m,1H),4.17(dd,J=11.5,5.8Hz,1H),4.09(dd,J=11.4,7.1Hz,1H), 3.97(dd,J=8.2,2.7Hz,1H),2.34(d,J=1.5Hz,1H),2.18(s,3H),2.18(s,3H),2.14(s,3H),2.06 (s,3H)。
Claims (8)
1.一种合成1,3,4,6-四乙酰基-L-古罗糖的方法,其特征在于该方法包括以下具体步骤:
a、用叔丁基二甲基氯硅烷保护化合物Ⅱ的伯羟基得到化合物Ⅲ;
b、以氢化钠为碱,使用苄基保护化合物Ⅲ的羟基得到化合物Ⅳ;
c、用四丁基氟化铵脱除硅保护基得到化合物Ⅴ;
d、通过戴斯马丁氧化或斯文氧化将化合物Ⅴ的伯羟基氧化为醛,得到化合物Ⅵ;
e、在酸性条件下脱除乙缩醛保护基使其自动闭环得到苄基取代的吡喃糖Ⅷ;
f、以吡啶做溶剂,用醋酐使吡喃糖Ⅷ的羟基乙酰化,得到化合物Ⅸ;
g、用催化氢化的方法脱除化合物Ⅸ的苄基保护,得到目标产物Ⅰ;其具体合成路线为:
2.根据权利要求1所述的方法,其特征在于所述步骤a中使用的溶剂为二氯甲烷或N,N-二甲基甲酰胺,叔丁基二甲基氯硅烷与化合物Ⅱ的摩尔比为1:1~1.5:1,所用碱为三乙胺或咪唑,反应温度0~25℃,反应时间为6~18h。
3.根据权利要求1所述的方法,其特征在于所述步骤b中所用溶剂为N,N-二甲基甲酰胺或四氢呋喃,所用碱为氢化钠,苄基化试剂为溴化苄,反应温度为0~40℃,反应时间6~24h;反应结束后,使用水淬灭反应。
4.根据权利要求1所述的方法,其特征在于所述步骤c中反应溶剂为四氢呋喃,四丁基氟化铵与化合物Ⅳ的摩尔比为1:1~3:1,反应温度0~40℃,反应时间为2~12h;反应结束后,通过使用石油醚、乙酸乙酯、二氯甲烷、甲苯中的一种或几种打浆,得到白色固体即化合物Ⅴ。
5.根据权利要求1所述的方法,其特征在于所述步骤d中所用氧化方法为戴斯马丁氧化或斯文氧化;反应结束后通过硅胶柱层析纯化得到化合物Ⅵ。
6.根据权利要求1所述的方法,其特征在于所述步骤e中所用酸为浓度0.1mol/L~2mol/L的盐酸或硫酸,反应温度110~140℃,反应时间为2~12h;反应结束后冷却至室温,继续搅拌12~36h;加入碳酸钡粉末或阴离子交换树脂至反应液中性,抽滤,旋干滤液,将所得粘稠液体直接投入下一步反应。
7.根据权利要求1所述的方法,其特征在于所述步骤f中所用的溶剂为吡啶,所用乙酰化试剂为醋酐,醋酐与化合物Ⅷ的摩尔比为5~20:1,反应温度为0~40℃,反应时间为6~24h;反应结束后,于-15℃~10℃下,用1M~3M盐酸溶液调反应液pH至酸性后用乙酸乙酯萃取2~3次,合并的有机相经水洗,饱和食盐水洗并干燥,浓缩溶剂后柱层析纯化得到混合物Ⅸ。
8.根据权利要求1所述的方法,其特征在于所述步骤g中催化氢化所用的催化剂为5~20%的Pd/C或Pd(OH)2/C,所用的溶剂为甲醇、乙醇或乙酸乙酯;反应温度为15~50℃,反应时间为2~36h;反应结束后,过滤反应液,滤液浓缩后直接得到目标产物Ⅰ即1,3,4,6-四乙酰基-L-古罗糖。
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