CN1065534C - 硫辛酰胺新合成方法 - Google Patents
硫辛酰胺新合成方法 Download PDFInfo
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- CN1065534C CN1065534C CN96116303A CN96116303A CN1065534C CN 1065534 C CN1065534 C CN 1065534C CN 96116303 A CN96116303 A CN 96116303A CN 96116303 A CN96116303 A CN 96116303A CN 1065534 C CN1065534 C CN 1065534C
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- acid amide
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- 238000000034 method Methods 0.000 title claims abstract description 9
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- 230000002194 synthesizing effect Effects 0.000 title description 3
- -1 6,8-dihalogenated lipoic acid ester Chemical class 0.000 claims abstract description 7
- 239000011734 sodium Substances 0.000 claims abstract description 7
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 6
- SRRKNRDXURUMPP-UHFFFAOYSA-N sodium disulfide Chemical compound [Na+].[Na+].[S-][S-] SRRKNRDXURUMPP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000002798 polar solvent Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 3
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- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 2
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- 239000012467 final product Substances 0.000 abstract 1
- LTHCSWBWNVGEFE-UHFFFAOYSA-N octanamide Chemical class CCCCCCCC(N)=O LTHCSWBWNVGEFE-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 238000004904 shortening Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 3
- TWVJXIWTBPZSLM-UHFFFAOYSA-N CCC(CC(CCCCC(=O)N)Cl)Cl Chemical compound CCC(CC(CCCCC(=O)N)Cl)Cl TWVJXIWTBPZSLM-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010021703 Indifference Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 238000009776 industrial production Methods 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000005477 standard model Effects 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
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Abstract
硫辛酰胺的合成方法由6，8-二卤代硫辛酸酯为起始原料经酰胺化，环化而成，本发明采用起始原料由醇钠作为催化剂在极性溶剂中迅速反应制得6，8-二卤代辛酰胺再与二硫化钠反应制得最终产品，该方法优点为降低了生产成本，缩短了生产时间且产品质量符合要求。
Description
本发明涉及药物合成更具体说涉及合成方法的改进。硫辛酰胺为维生素类的保肝药物，它的化学结构如下：
目前它的制备方法主要有三个途径。
1、以6，8-二硫辛酸为起始原料，酰胺化后制得硫辛酰胺(美国专利3223712)该方法工艺路线长，原料硫辛酸价格昂贵，不宜工业化。
2、6，8-二卤化辛酸为原料，经酰胺化再二硫化制得硫辛酰胺(日本特许公开昭482537)此方法使用二氯亚砜，五氯化磷等有毒试剂合成酰胺，步骤也比较长，故不宜生产。
3、依6，8-二卤代辛酸酯为起始原料，直接酰胺化，再二硫化制备成硫辛酰胺，本方法是目前工业应用的主要路线，直接由酯酰胺化，主要采用浓氨水室温酰胺化(美国专利3231590)反应时间长达五天，且受样品在溶剂中溶解度的影响，反应液中原料浓度较低，工业化生产时设备利用率不高，尚缺乏高效，快速和简便的方法。它的工艺流程如下：
1、胺化反应
本发明目的在于寻找出一种高效，快速并且简便能适合工业生产硫辛酰胺的新合成方法。
本发明通过下列反应式实施
其中反应式中X1，X2为相同或不相同的卤素原子，R，R2为C1-C5低烷基，R1为H。
首先用6，8-二卤代辛酸酯作为起始原料，在极性溶媒中通过醇钠的催化作用与低烷基酰胺反应生成6，8-二卤代辛酰胺。极性溶媒为在碱性条件下比较稳定的，能较好溶解原料6，8-二卤代辛酸酯的例如，甲醇、乙醇、四氢呋喃、二甲基甲酰胺等溶媒，溶剂量通常为原料量的1-20倍不等，醇钠的催化主要用甲醇钠、乙醇钠、异丙醇钠等简单醇钠作为催化剂，它的用量一般为相当于原料摩尔数的0．1-2倍，获得中间体6，8-二卤代辛酰胺再与二硫化钠反应即得硫辛酰胺(Ⅲ)。
本发明通过以下实施例进一步说明。
实施例1
140克6．8-二氯辛酸乙酯，112克甲酰胺，375毫升四氢呋喃依次加入反应烧瓶中，搅拌加热至75℃缓缓滴入25％(W／W)液体甲醇钠溶液112克，30分钟加毕，继续搅拌反应30分钟后冷却，加入100毫升水，用甲苯萃取三次，萃取液合并，水洗，减压回收甲苯，残溜液搅拌，滴加入石油醚，析出白色结晶，过滤、滤饼用少量石油醚洗涤，干燥得6，8-二氯辛酰胺95克，称取6，8-二氯辛酰胺5克，溶于18毫升乙醇中，缓缓滴入到由7．1克Na2S·9H2O，0．95克硫磺，42毫升乙醇而制得的二硫化钠溶液中，1小时内加毕，在70℃±5℃搅拌反应3小时，停止加温，加入25毫升5％ NaOH溶液，继续搅拌1小时，减压蒸去乙醇后加入40毫升5％ NaOH溶液，用甲苯提取四次，提取液浓缩至50毫升左右，放置，析出黄色结晶，过滤，水洗干燥得结晶3克，熔点124-126℃用无水乙醇重结晶，得黄色针状结晶，熔点127-129℃，与硫辛酰胺标准品测混合熔点不下降，经板层与标准样品比较显示斑点无差别。
Claims (1)
1、一种制备硫辛酰胺的方法，其特征在于反应通式为
其中X1，X2为相同或不相同的卤素原子，R，为C1-C5的低烷基，在极性溶剂中在醇钠R2ONa，其中R2为C1-C5低烷基的催化下与甲酰胺反应生成6，8-二卤代辛酰胺(Ⅱ)
其中X1和X2的定义同上，(Ⅱ)再与二硫化钠反应获得硫辛酰胺(Ⅲ)
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| Application Number | Priority Date | Filing Date | Title |
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| CN96116303A CN1065534C (zh) | 1996-04-03 | 1996-04-03 | 硫辛酰胺新合成方法 |
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| Application Number | Priority Date | Filing Date | Title |
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| CN96116303A CN1065534C (zh) | 1996-04-03 | 1996-04-03 | 硫辛酰胺新合成方法 |
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| Publication Number | Publication Date |
|---|---|
| CN1161332A CN1161332A (zh) | 1997-10-08 |
| CN1065534C true CN1065534C (zh) | 2001-05-09 |
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| CN96116303A Expired - Fee Related CN1065534C (zh) | 1996-04-03 | 1996-04-03 | 硫辛酰胺新合成方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100436444C (zh) * | 2006-07-29 | 2008-11-26 | 常熟富士莱医药化工有限公司 | 硫辛酰胺合成工艺 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3231590A (en) * | 1959-12-28 | 1966-01-25 | Takeda Pharmaceutical | N?-(6, 8-dichlorooctanoyl)-l-lysine |
| SU457704A1 (ru) * | 1973-12-27 | 1975-01-25 | Всесоюзный Научно-Исследовательский Витаминный Институт | Способ получени амида липоевой кислоты |
| SU527432A1 (ru) * | 1974-11-10 | 1976-09-05 | Всесоюзный Научно-Исследовательский Витаминный Институт | Способ получени амида липоевой кислоты |
-
1996
- 1996-04-03 CN CN96116303A patent/CN1065534C/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3231590A (en) * | 1959-12-28 | 1966-01-25 | Takeda Pharmaceutical | N?-(6, 8-dichlorooctanoyl)-l-lysine |
| SU457704A1 (ru) * | 1973-12-27 | 1975-01-25 | Всесоюзный Научно-Исследовательский Витаминный Институт | Способ получени амида липоевой кислоты |
| SU527432A1 (ru) * | 1974-11-10 | 1976-09-05 | Всесоюзный Научно-Исследовательский Витаминный Институт | Способ получени амида липоевой кислоты |
Non-Patent Citations (1)
| Title |
|---|
| 《药学杂志》VOL.81.NO.6 1961.1.1 Toyokaxu Kishi:New Sgnthesis of d-hipamide * |
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| Publication number | Publication date |
|---|---|
| CN1161332A (zh) | 1997-10-08 |
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