CN1018831B - 新型抗坏血酸酯的制备方法 - Google Patents
新型抗坏血酸酯的制备方法Info
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Abstract
通过于惰性有机溶剂中用酸处理2-酮-L-古洛糖酸并自反应混合物中回收得到的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯基本上不含有2-酮-L-古洛糖酸。6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯较L-抗坏血酸更具有脂溶性,因而可用作为肠道所吸收的L-抗坏血酸之前药。
Description
本发明涉及新型抗坏血酸酯及其制备方法。
作为一种生产L-抗坏血酸的已知方法,是使用2-酮-L-古洛糖酸或其丙酮或双丙酮衍生物作为原料[例如,美国专利2,185,383(1940),日本审查专利公开48-15931(1973),PCTWO87/00839(1987)]。这些发明人发现,自这些已知生产方法的反应混合物中可得到一种新型化合物,由反应混合物中可成功地分离得到基本上不含原料的新型化合物。他们还发现,若用碱处理这种化合物,则1摩尔这种新型化合物可生成2摩尔L-抗坏血酸。本发明就是基于这些发现来完成的。
因此,本发明涉及(1)基本上不含有2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯,和(2)制备不含2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯之方法,该方法包括于惰性有机溶剂中用酸处理2-酮-L-古洛糖酸或其酮缩醇直至反应混合物中生成大量的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯为止,然后分离出6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。
通过2-酮-L-古洛糖酸或其酮缩醇的反应可制备上述酯,这一反应须在无机酸如盐酸存在下于惰性有机溶剂(如苯、甲苯)中和室温-70℃,以60-70℃为佳的温度范围内进行。提高酯产率的方法包括在反应混合物中加入少量酸(约占原料重量的0.1-2%)和少量水(约占原料重量的0.5-5%)。
可采用吸附剂分离出反应混合物中基本上不含2-酮-L-古洛糖酸的新型化合物6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。这类吸附剂包括合成多孔树脂如大网状树脂-Ⅱ(Organo公司生产)。采用这种吸附剂分离6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯的方法如下:将反应混合物加至水中,静置后分出水层。然后使水层通过一个填充有大网状树脂-Ⅱ的柱,用水洗提所需的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。之所以能够分离并回收6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯,其原因在于未反应的原料2-酮-L-古洛糖酸能比上述酯更快地被洗提下来,合并洗提液并将其浓缩至干或冻干,可得到基本上不含有2-酮-L-古洛糖酸的6-O(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。
硅胶也可用作回收上述反应混合物中6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯的吸附剂,采用这种吸附剂,便可分离得到基本上不含有2-酮-L-古洛糖酸和L-抗坏血酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯,也就是说,将反应混合物浓缩至干,使残渣溶于丙酮/苯(约1∶1,V/V)的混合物中,使此溶液通过一填充有硅胶的柱中,用丙酮和苯所形成的混合物洗提所需化合物。
将含有6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯的馏分合并后,经过浓缩便可得到基本上不含2-酮-L-古洛糖酸和L-抗坏血酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。
举例来说,可使用上述吸附剂纯化通过上述方法获得的、基本上不含2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。
对实施例1中所得到的酯进行元素分析,结果为:
分析C12H16O12·H2O
理论值:C:38.93,H:4.90
实测值:C:38.77,H:4.84
这种酯的红外吸收光谱、′H-核磁共振谱、C-核磁共振谱、和紫外吸收光谱分别示于表1-4。
根据元素分析、各种光谱化学分析及质谱分析结果可知,实施例1中分离得到的酯是6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。
基本上不含有本发明2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯可水解为L-抗坏血酸。
水解可借助于碱性物质,特别是弱碱性物质来完成,例如处于水或含水有机溶剂(低级醇如甲醇,乙醇,丙醇;酮如丙酮,甲乙酮;腈如乙腈,丙腈)中的碳酸氢钠和碳酸氢钾。碱性物质的用量一般为1-10mol,以1-7mol为佳。反应温度为20-70℃,以25-60℃为佳,反应时间一般为1-6小时。
为了自2-酮-L-古洛糖酸的酯类如甲酯制备L-抗坏血酸,反应须采用强碱性物质如氢氧化钠和甲醇钠在基本上无水的溶剂中进行。然而,本发明的酯的水解及闭环反应基本上是利用处于水或含水溶剂中进行的,并且可由1mol原料化合物制备2molL-抗坏血酸。既使是在日本药典Ⅺ中所述分解试验(PH=6.8)的溶液B中也可由本发明的新型酯制备L-抗坏血酸。
基本上不含本发明2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯,由于其中的酯键要比L-抗坏血酸更具有脂溶性,并且既使在日本药典Ⅺ中所述分解试验的溶液B中也易于水解,得到L-抗坏血酸;因此,可以用其作为生产L-抗坏血酸的前药,而L-抗坏血酸又可通过肠道被吸收。
此外,在温和条件下,基本上不含本发明2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯可用来高产率地制备大量L-抗坏血酸。
下列实施例可对本发明作更详细的描述。
实施例1
将20g(68.5mmol)双丙酮-2-酮-L-古洛糖酸-水合物加至60ml甲苯中,并于40℃下搅拌。然后加入1ml35%的盐酸并搅拌5小时。反应完毕,减压蒸除溶剂,将残渣溶于80ml由丙酮与苯(1∶1,V/V)所组成的混合物中。使该溶液以0.5的空间速度通过填充有600ml硅胶的柱(直径为4cm,长度为50cm)。分别用1.2升1∶1(V/V),1.2升1∶5(V/V),1.2升1∶1(V/V)和3升5∶1(V/V)由丙酮和苯所组成的混合物以1-1.5的空速进行洗提。合并用5∶1(V/V)丙酮/苯混合物洗提得到的馏分并于减压下浓缩至干燥。将残渣溶于50ml水中,并使其通过由1.51大网状树脂-Ⅱ所构成的柱子。用水洗提后,合并含6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯的馏份,然后将其冻干。这样可获得14.5g基本上不含2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯(产率:60%)。
1H-NMR(400MHz,DMSO-d6)
δ:11.19(s,1H),8.41(s,1H),6.58(s,1H),5.34
(d,1H,J=5.9Hz),4.96(d,1H,J=5Hz),4.86
(d,1H,J=3Hz),4.74(d,1H,J=1.7Hz),4.16
(dd,1H,J=6.7Hz,10.4Hz),4.06
(dd,1H,J=7.0Hz,10.4Hz)
13C-NMR(400MHz,DMSO-d6)
δ:170.24(s),169.03(s),151.13(s),118.07(s),96.39(s),74.52(d),73.65(d),72.68(d),69.79(s),64.95(d),64.95(d),64.95(t),62.85(t)
IR(KBr盘)
V最大(cm-1)3370,1760,1700,1690,1280,1040
UV(H2O)
λ最大(ε):260(9300)
质量(SIMS)
M/e:352
由该实施例获得的基本上不含2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯,其红外吸收光谱图,1H-核磁共振谱图,13C-核磁共振谱图和紫外吸收光谱图分别示于图1-4。
实施例2
将20g(纯度:99.5%,103mmol)2-酮-L-古洛糖酸和90mg硬脂酰基丙邻二胺二油酸酯加至90ml甲苯之中,并于65℃下搅拌。向其中加入1.5ml浓盐酸。然后按照与实施例1相同的方法进行处理,可得到15.6g(43%)基本上不含有2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。
参考实施例1
将1.2g(3.4mmol)基本上不含2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯溶于50ml水中,再加入1.4g(17mmol)碳
酸氢钠,于40℃下搅拌约1.5小时。对该反应混合物进行高性能液相色谱分析,结果表明得到1.14g(产率:95.2%)L-抗坏血酸和0.07g2-酮-L-古洛糖酸,不过其中未发现有原料6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。进行高性能液相色谱分析的条件是:
柱:由BioRad公司制造的HPX-87H
流动相:0.1M硫酸铵
检测:差示析光计
参考实施例2
将1.2g(3.4mmol)6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯(基本上不含有2-酮-L-古洛糖酸)溶于50ml水中,加入由1.8g(8.5mmol)碳酸钠与5ml水所组成的溶液,于40℃下搅拌2小时。按照参考实施例1所述的方法对该反应混合物进行定量分析,结果表明得到1.10g(产率:91.9%)L-抗坏血酸和0.05g2-酮-L-古洛糖酸。
参考实施例3
将141mg基本上不含有2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯溶于100ml日本药典Ⅺ中分解试验的溶液B中(将6.804g-碱价磷酸钾溶于23.6ml1N氢氧化钠,然后加入水使其体积达11,PH=6.78),并于37℃下搅拌。对该反应混合物进行高性能液相色谱分析,获得如下结果。
反应时间 产率%(重量)
2 77
4 84
Claims (1)
1、一种制备基本上不含有2-酮-L-古洛糖酸的6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯的方法,其中包括在惰性有机溶剂内使盐酸与2-酮-L-古洛糖酸或其酮缩醇相互作用,直至反应混合物中主要成份为6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯为止,然后分离出6-O-(2-酮-L-古洛糖酰基)-L-抗坏血酸酯。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP148374/87 | 1987-06-15 | ||
JP14837487 | 1987-06-15 |
Publications (2)
Publication Number | Publication Date |
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CN1030235A CN1030235A (zh) | 1989-01-11 |
CN1018831B true CN1018831B (zh) | 1992-10-28 |
Family
ID=15451332
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN88103639A Expired CN1018831B (zh) | 1987-06-15 | 1988-06-15 | 新型抗坏血酸酯的制备方法 |
Country Status (11)
Country | Link |
---|---|
US (1) | US4845246A (zh) |
EP (1) | EP0295841B1 (zh) |
KR (1) | KR890000455A (zh) |
CN (1) | CN1018831B (zh) |
AT (1) | ATE63909T1 (zh) |
CA (1) | CA1296345C (zh) |
DE (1) | DE3863009D1 (zh) |
DK (1) | DK320188A (zh) |
ES (1) | ES2032967T3 (zh) |
GR (1) | GR3002033T3 (zh) |
IE (1) | IE61366B1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US7842723B2 (en) * | 2002-10-04 | 2010-11-30 | Bioderm Research | Ascorbic acid—natural sugar lactone esters for comprehensive skin and scalp care |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2185383A (en) * | 1937-04-28 | 1940-01-02 | Charles Pflzer & Company | Preparation of levo-ascorbic acid |
US4111958A (en) * | 1977-06-03 | 1978-09-05 | Pfizer Inc. | Ascorbic acid synthesis |
DD141832A1 (de) * | 1978-10-31 | 1980-05-21 | Joachim Schmidt | Verfahren und vorrichtung zur herstellung von l-ascorbinsaeure |
CN86105960A (zh) * | 1985-08-09 | 1987-05-13 | 鲁布里佐尔公司 | 在基本无水条件下从2-酮-l-古洛糖酸制备l-抗坏血酸 |
-
1988
- 1988-06-10 US US07/205,094 patent/US4845246A/en not_active Expired - Fee Related
- 1988-06-13 EP EP19880305362 patent/EP0295841B1/en not_active Expired - Lifetime
- 1988-06-13 AT AT88305362T patent/ATE63909T1/de not_active IP Right Cessation
- 1988-06-13 DE DE8888305362T patent/DE3863009D1/de not_active Expired - Fee Related
- 1988-06-13 CA CA000569304A patent/CA1296345C/en not_active Expired - Lifetime
- 1988-06-13 DK DK320188A patent/DK320188A/da not_active Application Discontinuation
- 1988-06-13 ES ES198888305362T patent/ES2032967T3/es not_active Expired - Lifetime
- 1988-06-14 IE IE179288A patent/IE61366B1/en not_active IP Right Cessation
- 1988-06-15 CN CN88103639A patent/CN1018831B/zh not_active Expired
- 1988-06-15 KR KR1019880007191A patent/KR890000455A/ko not_active Application Discontinuation
-
1991
- 1991-05-30 GR GR91400691T patent/GR3002033T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
DE3863009D1 (de) | 1991-07-04 |
US4845246A (en) | 1989-07-04 |
CA1296345C (en) | 1992-02-25 |
ES2032967T3 (es) | 1993-03-01 |
DK320188A (da) | 1988-12-16 |
ATE63909T1 (de) | 1991-06-15 |
KR890000455A (ko) | 1989-03-14 |
GR3002033T3 (en) | 1992-12-30 |
IE61366B1 (en) | 1994-11-02 |
DK320188D0 (da) | 1988-06-13 |
CN1030235A (zh) | 1989-01-11 |
EP0295841A1 (en) | 1988-12-21 |
EP0295841B1 (en) | 1991-05-29 |
IE881792L (en) | 1988-12-15 |
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