CN116903498A - 一种依卡倍特钠的合成方法 - Google Patents
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 14
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims abstract description 11
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 claims abstract description 10
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007670 refining Methods 0.000 claims abstract description 6
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- 239000003960 organic solvent Substances 0.000 claims description 5
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- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- QUUCYKKMFLJLFS-UHFFFAOYSA-N Dehydroabietan Natural products CC1(C)CCCC2(C)C3=CC=C(C(C)C)C=C3CCC21 QUUCYKKMFLJLFS-UHFFFAOYSA-N 0.000 description 4
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- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 3
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/06—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with sulfuric acid or sulfur trioxide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
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Abstract
本发明涉及一种依卡倍特钠的合成方法。以歧化松香为起始原料，经过磺化和成盐得到依卡倍特钠粗品，依卡倍特钠粗品经过精制得到依卡倍特钠。本发明方法原料易得，合成路线简短，产生三废少，产物收率高；适合工业化生产。
Description
技术领域
本发明涉及一种依卡倍特钠的合成方法。属于有机化合物制备技术领域。
背景技术
依卡倍特钠（Ecabet Sodium Granules），化学名为 (+)-(1R,4aS,10aR)-1,2,3,4a,9,10,10a-八氢-1,4a-二甲基-7-(1-甲基乙基)-6-磺酸-1-菲羧酸- 6-钠盐五水合物，商品名盖爽，由日本田边制药有限公司研发，临床上用于治疗胃粘膜损伤(糜烂、出血、红肿、水肿)，急性胃炎、慢性胃炎的急性发作期和胃溃疡。依卡倍特钠的结构式如下式1所示。
式1 依卡倍特钠化学结构式
依卡倍特钠主要的合成方法如下：
文献J Am Chem Soc 1938, 602631、Drugs Fut 1988，13（11）, 966和Chem PharmBuII 1985, 33（4）, 1472报道了采用脱氢枞酸为起始原料，经过与硫酸磺化反应，得到依卡倍特酸，再在氢氧化钠水溶液中成盐得到依卡倍特钠粗品，经过多次重结晶得到依卡倍特钠成品，反应路线如下：
该方法磺化反应速度慢，且转化不完全，依卡倍特钠粗品需要经过多次重结晶才能够得到符合药用标准的依卡倍特钠。
CN104086465B公布了同样采用脱氢枞酸为起始原料，采用发烟硫酸为磺化试剂，得到依卡倍特酸，依卡倍特酸采用异辛酸钠或者碳酸钠水溶液成盐得到依卡倍特钠粗品，依卡倍特钠粗品经过醇/水体系或者丙酮/水体系精制得到依卡倍特钠。该方法采用发烟硫酸进行磺化，工业大生产危险系数高，成盐采用异辛酸钠或者碳酸钠水溶液，成本高，依卡倍特钠粗品用有机溶剂/水体系重结晶，存在依卡倍特钠溶剂化物的风险。
而脱氢枞酸的生产采用松香酸为起始原料经过歧化反应得到歧化松香，歧化松香需要经过与乙醇胺成盐、精制以及游离等步骤得到脱氢枞酸，过程产生大量的三废。
鉴于此，本发明以歧化松香为起始原料，采用有机溶剂/浓硫酸体系磺化，得到依卡倍特酸，依卡倍特酸采用氢氧化钠水溶液成盐得到依卡倍特钠粗品，依卡倍特钠粗品采用纯化水重结晶得到依卡倍特钠。大大缩短了路线的长度，从而提高反应总收率（反应总收率65.6%）；同时避免了起始原料的纯化、以及采用危险系数高的发烟硫酸，整个合成工艺更加的环保以及适合工业化生产。
发明内容
本发明的目的是公开一种依卡倍特钠（Ⅰ）的合成方法。旨在克服现有技术所存在的上述缺陷。
本发明的另一目的为公开该类型化合物的制备方法。
一种依卡倍特钠的合成（Ⅰ）可通过下述方法制备得到：
该方法包括如下工艺步骤：
(a) 以歧化松香为起始原料，与硫酸在一定条件下反应得到依卡倍特酸（II）。
(b) 依卡倍特酸（II）与氢氧化钠在一定条件下反应得依卡倍特钠粗品（III），粗品经过精制条件得到依卡倍特钠（I）。
在一个实施方案中， 步骤(a) 有机溶剂为有机溶剂为正己烷、正庚烷、石油醚或其任意混合物，优选正己烷；硫酸为浓硫酸；所述的依卡倍特酸（II）的制备可以采取以下方法：正己烷为溶剂，浓硫酸与歧化松香反应完全后，加入至水中淬灭反应，过滤，无需纯化可直接用于下步反应。反应条件为歧化松香、浓硫酸和正己烷的质量比为1.0：1.0-:4.0：1.0-4.0，优选1.0:2.5:2.5；反应温度为-20-50℃，优选10-20℃。
在一个实施方案中，步骤(b)溶剂为纯化水；氢氧化钠水溶液的浓度为5%~50%，优选浓度为40%。所述的依卡倍特钠粗品（II）的制备可以采取以下方法：水作为溶剂，40%的氢氧化钠水溶液作为钠剂，调节pH完成后，升温反应，降温析晶，过滤，干燥得到依卡倍特钠粗品（II），依卡倍特钠粗品经过纯化水精制得到依卡倍特钠。反应条件为歧化松香与水的质量比为1.0:5.0-15.0，优选1.0:10.0；调节pH温度为10-95℃，优选不过50℃；升温反应温度为10-95℃，优选80℃；析晶温度为5-35℃，优选30℃。精制析晶温度为5-35℃，优选30℃。
附图说明
图1为实施例3制备得到的依卡倍特钠氢谱；
图2实施例3制备得到的依卡倍特钠HPLC检测图谱。
具体实施方式
实施例1：依卡倍特酸（Ⅲ）的制备
在装有机械搅拌的500mL的三口瓶中加入正己烷100ml，浓硫酸100g，搅拌下降温至0~5℃，缓慢加入歧化松香40g，控制温度不超过20℃，加毕，10~20℃反应30分钟，将反应液加入至320g冰水中，加毕搅拌10分钟，抽滤，滤饼用适量水洗涤，得到湿品直接用于下一步反应。
实施例2：依卡倍特钠粗品（I）的制备
在装有机械搅拌的1000mL的三口瓶中加入水400g，实施例1所得湿品全量，用40%氢氧化钠水溶液调节pH至3~4，控制温度不超过50℃，调节完成，升温至80℃搅拌1小时，降温至30℃，抽滤，滤饼用适量水洗涤，60℃干燥得到依卡倍特钠45g，收率68.6%。
实施例3：依卡倍特钠（I）的制备
在装有机械搅拌的500mL的三口瓶中，加入水350ml，依卡倍特钠粗品45g，加热至回流，溶清后搅拌降温至30℃，抽滤，滤饼用适量水洗涤，65℃干燥得到依卡倍特钠43g，收率95.6%。核磁氢谱见图1，所述核磁氢谱的结果为：
1H-NMR (500 MHz, DMSO-d6) δ: 7.67(1H, s), 6.93(1H, s), 4.06(1H, m),2.86(1H, dd), 2.76(1H, m), 2.26(1H, d), 2.02(1H, dd), 1.79(4H, m), 1.59(1H,m), 1.43(1H, m), 1.39(1H, m), 1.17(3H, s), 1.13(9H, m)
HPLC检测图谱见图2；由图2可知，利用所述制备方法制备得到的依卡倍特钠的HPLC纯度为99.9527%。
Claims (6)
1.一种依卡倍特钠（Ⅰ）的合成方法：
根据权利要求书1所述的一种依卡倍特钠的合成方法，其特征在于包括下列步骤：
(a) 以歧化松香为起始原料，与硫酸在一定条件下反应得到依卡倍特酸（II）；
(b) 依卡倍特酸（II）与氢氧化钠在一定条件下反应得依卡倍特钠粗品（III），粗品经过精制条件得到依卡倍特钠（I）；
2.根据权利要求2中所述的方法，其特征在于，步骤(a)具体为：
(Ⅰ)步骤（a）中所述的硫酸为浓硫酸。
3.(Ⅱ)步骤（a）所述的一定条件为无溶剂或有机溶剂存在下，在一定温度下反应。有机溶剂为正己烷、正庚烷、石油醚或其任意混合物；一定温度为-20-50℃。
4.根据权利要求2所述的方法，其特征在于，步骤(b)具体为：
(Ⅰ) 步骤（b）中所述的氢氧化钠为5%~50%的氢氧化钠水溶液。
5.(Ⅱ) 步骤（b）所述的一定条件为无溶剂或有溶剂存在下，在一定温度下反应。溶剂为水；一定温度为10-95℃。
6.(Ⅲ) 步骤（b）所述的精制条件为无溶剂或溶剂存在下，在一定温度下析晶。溶剂为纯化水；析晶温度为5-35℃。
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